Vol. 52, Issue 1, 11-34, March 2000

Molecular and Cellular Mechanisms of Angiotensin II-Mediated Cardiovascular and Renal Diseases

Department of Pharmacology, Osaka City University Medical School, Abeno-ku, Osaka, Japan

I. Introduction
II. Classification and Biochemical Characteristics of Angiotensin Receptors
    A. AT₁ Receptor
    B. AT₂ Receptor
III. Molecular and Cellular Actions of Angiotensin II in Heart
    A. Molecular Characteristics of Pathological Cardiac Hypertrophy
    B. Cultured Cardiac Myocytes
    C. Neonatal versus Adult Cardiac Myocytes
    D. Cultured Cardiac Fibroblasts
    E. Effects of In Vivo Angiotensin II Infusion on Heart
    F. Effects of Angiotensin Blockade on Experimental Cardiac Diseases
        1. Spontaneously Hypertensive Rats and Other Hypertensive Models.
        2. Acute Pressure Overload Model.
        3. Myocardial Infarction.
        4. Volume Overload Model.
        5. Diabetes.
IV. Molecular and Cellular Actions of Angiotensin II in Blood Vessels
    A. Cultured Smooth Muscle Cells
    B. Cultured Endothelial Cells
    C. Effects of In Vivo Angiotensin II Infusion on Vascular Tissues
    D. Effects of Angiotensin Blockade on Experimental Vascular Diseases
        1. Hypertensive Rats.
        2. Balloon Injury.
        3. Other Models.
V. Molecular and Cellular Actions of Angiotensin II in Kidney
    A. Cultured Glomerular Cells
    B. Effects of In Vivo Angiotensin II Infusion on Kidney
    C. Effects of Angiotensin Blockade on Experimental Glomerular Diseases
VI. AT₁ Receptor Antagonists versus Angiotensin-Converting Enzyme Inhibitors
    A. Pharmacological Differences
    B. Is the AT₂ Receptor Beneficial or Detrimental?
    C. Combination Therapy
VII. Conclusions
Acknowledgments
References

	Abstract

Top References

A growing body of evidence supports the notion that angiotensin II (Ang II), the central product of the renin-angiotensin system, may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiovascular and renal diseases in humans. In this review, we focus on the role of Ang II in cardiovascular and renal diseases at the molecular and cellular levels and discuss up-to-date evidence concerning the in vitro and in vivo actions of Ang II and the pharmacological effects of angiotensin receptor antagonists in comparison with angiotensin-converting enzyme inhibitors. Ang II, via AT₁ receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances (vasoactive hormones, growth factors, extracellular matrix components, cytokines, etc.), and activates multiple intracellular signaling cascades (mitogen-activated protein kinase cascades, tyrosine kinases, various transcription factors, etc.) in cardiac myocytes and fibroblasts, vascular endothelial and smooth muscle cells, and renal mesangial cells. These actions are supposed to participate in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, atherosclerosis, and glomerulosclerosis. Furthermore, in vivo recent evidence suggest that the activation of mitogen-activated protein kinases and activator protein-1 by Ang II may play the key role in cardiovascular and renal diseases. However, there are still unresolved questions and controversies on the mechanism of Ang II-mediated cardiovascular and renal diseases.

	I. Introduction

Top Next References

Classically, angiotensin II (Ang II),² the central product of the renin-angiotensin system (Fig. 1), is well known to cause potent increases in systemic and local blood pressure via its vasoconstrictive effect, to influence renal tubules to retain sodium and water, and to stimulate aldosterone release from the adrenal gland (Timmermans et al., 1993). A growing body of evidence, from pharmacological investigations and clinical studies on the effects of angiotensin-converting enzyme (ACE) inhibitors, supports the notion that Ang II may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, atherosclerosis, and glomerulosclerosis in humans. An excellent and comprehensive review on pharmacology of angiotensin receptor antagonists was published in 1993 (Timmermans et al., 1993). However, since then, a great number of in vitro and in vivo findings on the functions of Ang II have emerged, showing that Ang II directly causes cell growth, regulates the gene expression of various bioactive substances [vasoactive hormones, growth factors, extracellular matrix (ECM) components, cytokines, and so on], and activates multiple intracellular signaling cascades [mitogen-activated protein (MAP) kinase cascades, tyrosine kinases, various transcription factors, and so on] in cardiovascular and renal cells. Furthermore, accumulating in vivo evidence supports the notion that Ang II may directly cause cardiovascular and renal diseases, independent of its blood pressure-elevating effect. Thus, recent in vivo work, coupled with in vitro findings, has provided new insights into the molecular and cellular mechanisms of Ang II-mediated cardiovascular and renal diseases. In this review, we focus on the role of Ang II in cardiovascular and renal diseases at the molecular and cellular levels and discuss up-to-date evidence concerning the actions of Ang II and the pharmacological effects of angiotensin receptor antagonists. Furthermore, we discuss recent progress, clearly separating the in vitro and in vivo evidence, because previous data have largely come from in vitro studies using cultured cells, and most of these data have not yet been demonstrated to apply to in vivo conditions.

View larger version (30K): [in this window] [in a new window]   Fig. 1.   Cascade of renin-angiotensin system. ACE, angiotensin-converting enzyme; AT1, AT1 receptor; AT2, AT2 receptor.

	II. Classification and Biochemical Characteristics of Angiotensin Receptors

Top Previous Next References

A. AT₁ Receptor

Excellent detailed reviews, dealing with biochemical properties and molecular biology of angiotensin receptors, have been published previously (Brown and Sernia, 1994; Unger et al., 1996). Therefore, in this review, we only briefly discuss the characteristics of angiotensin receptors. The existence of two subtypes of Ang II receptors, including Ang II types 1 and 2 (AT₁ and AT₂) receptors (Fig. 1), was first confirmed by a pharmacological approach using various specific Ang II receptor antagonists (Chiu et al., 1989). The successful cloning of AT₁ receptor in 1991 (Murphy et al., 1991; Sasaki et al., 1991) allowed the development of further research on the structure and function of this receptor. In rats or mice, AT₁ receptor consists of two subtypes, AT_1a and AT_1b, which have 94% homology with regard to amino acid sequence and have similar pharmacological properties and tissue distribution patterns. AT₁ receptor is a member of the seven transmembrane-spanning, G protein-coupled receptor family; binds to heterotrimeric G proteins; and lacks intrinsic tyrosine kinase activity. Human AT₁ receptor gene is mapped to chromosome 3, and AT_1a and AT_1b receptor genes in rats are mapped to chromosomes 17 and 2, respectively. AT₁ receptor is ubiquitously and abundantly distributed in adult tissues, including blood vessel, heart, kidney, adrenal gland, liver, brain, and lung. AT₁ receptor mediates all the classic well known effects of Ang II, such as elevation of blood pressure, vasoconstriction, increase in cardiac contractility, aldosterone release from the adrenal gland, facilitation of catecholamine release from nerve endings, renal sodium and water absorption, and so on, as reviewed previously in detail (Timmermans et al., 1993). In addition, recent accumulating in vitro and in vivo evidence supports the notion that Ang II, mediated by AT₁ receptor, may participate directly in the pathogenesis of various cardiovascular and renal diseases, and this evidence is the focus of this review. Thus, the molecular and cellular actions of Ang II in cardiovascular and renal diseases are almost exclusively mediated by AT₁ receptor. Numerous selective and potent nonpeptide AT₁ receptor antagonists have been developed, such as losartan, candesartan, valsartan, irbesartan, eprosartan, telmisartan, tasosartan, and others, and in recent years, several of these compounds, including losartan, candesartan, valsartan, and others, have been in use clinically for the treatment of hypertension (Bauer and Reams, 1995; Johnston, 1995; Pitt and Konstam, 1998).

B. AT₂ Receptor

Molecular cloning, structural features, regulation of gene expression, and the possible functions of AT₂ receptor have been reviewed elsewhere (Unger et al., 1996; Matsubara, 1998). Selective AT₂ receptor ligands include PD123177, PD123319, CGP42112, L-162,686, L-162,638, EXP801, and CGP42112A. The cDNA and genomic DNAs of human, rat, and mouse AT₂ receptors have been cloned. AT₂ receptor is ubiquitously expressed in developing fetal tissues, suggesting a possible role of this receptor in fetal development and organ morphogenesis. In contrast, AT₂ receptor expression rapidly decreases after birth, and in the adult, expression of this receptor is limited mainly to the uterus, ovary, certain brain nuclei, heart, and adrenal medulla. The AT₂ receptor gene is localized as a single copy on the X chromosome. Unlike the AT₁ receptor, which has been shown to have subtypes in rats and mice, there is no evidence for subtypes of the AT₂ receptor. Although a comparison of amino acid sequences of AT_1a and AT₂ receptors in rats, deduced from nucleotide sequences, shows a low homology between these receptors (32%), AT₂ receptor is also a seven-transmembrane domain receptor. Recent work showed that AT₂ receptor is coupled to the G protein G_i (Hayashida et al., 1996; Zhang and Pratt, 1996). In various cell lines, AT₂ receptor-activated protein tyrosine phosphatase was shown to inhibit cell growth (Matsubara, 1998) or induce programmed cell death (apoptosis) (Yamada et al., 1996). AT₂ receptor inhibited AT₁ receptor-mediated cell growth, demonstrating an antagonistic action. However, there have also been conflicting findings regarding these receptors. In contrast to extensive data on the molecular and cellular functions and pathophysiological significance of AT₁ receptor, the role of AT₂ receptor in cardiovascular and renal diseases remains to be defined. At present, an AT₂ receptor ligand has not been developed for clinical use. However, because up-to-date evidence suggests that AT₂ receptor may contribute to the pharmacological differences between AT₁ receptor antagonists and ACE inhibitors, we discuss the potential functional role of AT₂ receptor in VI. AT₁ Receptor Antagonists versus Angiotensin-Converting Enzyme Inhibitors.

	III. Molecular and Cellular Actions of Angiotensin II in Heart

Top Previous Next References

A. Molecular Characteristics of Pathological Cardiac Hypertrophy

We first discuss the characteristics of pathological cardiac hypertrophy as background for understanding the role of Ang II in cardiac diseases. The characteristics of pathological cardiac hypertrophy have been reviewed in detail previously (Schwartz et al., 1993; Parker, 1995). Generally, pathological left ventricular hypertrophy is characterized not only by an increase in myocyte size (quantitative change) but also by myocyte gene reprogramming (qualitative change), as shown by enhanced expression of fetal phenotypes of genes such as -myosin heavy chain (-MHC), skeletal -actin, and atrial natriuretic factor (ANF). In the cardiac ventricle of most mammalian species, including humans, MHC consists of two isoforms: - and -MHCs. In the rat, -MHC is the predominant isoform in adult hearts (Lompre et al., 1984), has high Ca²⁺ and actin-activated ATPase activity, and is associated with increased shortening velocity of the cardiac fibers (Barany, 1967; Alpert and Mulieri, 1982). On the other hand, -MHC is the predominant isoform in fetal hearts (Lompre et al., 1984), has lower ATPase activity, and is associated with slower shortening velocity (Barany, 1967; Alpert and Mulieri, 1982). Therefore, changes in the ratio of -MHC (fetal phenotype) to -MHC (adult phenotype) in the cardiac ventricle significantly alter the contractile properties of the heart. Cardiac sarcomeric actin is also composed of two isoforms: cardiac -actin and skeletal -actin. Cardiac -actin is predominantly expressed in adult rat hearts, whereas skeletal -actin is normally expressed in fetal and neonatal rat hearts (Minty et al., 1982; Mayer et al., 1984). Because skeletal -actin has greater contractility than cardiac -actin (Hewett et al., 1994), the ratio of skeletal -actin to cardiac -actin in the ventricle plays a significant role in cardiac function. Thus, an increase in ventricular myocyte expression of fetal isoforms of contractile proteins (-MHC and skeletal -actin), which often occurs in the hypertrophic heart (Schwartz et al., 1986; Izumo et al., 1987), modulates cardiac performance. Furthermore, in addition to showing enhanced expression of -MHC and skeletal -actin, hypertrophic ventricular myocytes are also characterized by significant up-regulation of ANF (Izumo et al., 1988), which is scarcely expressed in normal adult ventricular myocytes.

Another important property of pathological cardiac hypertrophy is increased accumulation of ECM proteins such as collagen (particularly collagen types I and III) and fibronectin in the interstitium and around blood vessels within the heart. These changes play a central role in ventricular fibrosis or remodeling. The detailed characteristics and significance of these processes have been reviewed elsewhere (Brilla et al., 1992; Pelouch et al., 1993; Weber et al., 1994b; Weber, 1997). Increased interstitial collagen deposition in the heart enhances cardiac stiffness (Abrahams et al., 1987; Doering et al., 1988; Jalil et al., 1989) and results in diastolic dysfunction (Pelouch et al., 1993; Weber et al., 1994b). Fibronectin is localized on the surface of cardiac myocytes, connects cardiac myocytes to perimyocytic collagen (Ahumada and Saffitz, 1984), and is thought to affect cardiac systolic and diastolic functions. Thus, increased ECM accumulation, as well as the above-mentioned ventricular myocyte gene reprogramming, plays a critical role in the impairment of cardiac performance and pathophysiology of cardiac failure. ECM proteins within the heart are predominantly produced by fibroblasts. Notably, unlike cardiac myocytes, cardiac fibroblasts proliferate and increase the production of ECM proteins when the heart is exposed to hypertrophic stimuli such as hemodynamic overload. Thus, cardiac fibroblasts and cardiac myocytes play key roles in the development of pathological cardiac hypertrophy and dysfunction. Accumulating in vitro and in vivo evidence supports the concept that Ang II is involved in all of these important processes of pathological cardiac hypertrophy, including myocyte hypertrophy, myocyte gene reprogramming, fibroblast proliferation, and ECM protein accumulation, as described later.

B. Cultured Cardiac Myocytes

The molecular mechanism of hypertrophy of cultured cardiac myocytes has been extensively studied, mostly using neonatal rat cardiac myocytes, and was reviewed recently (Baker et al., 1992; Sadoshima and Izumo, 1997; Sugden and Clerk, 1998a). In this article, we briefly discuss the effects of Ang II on cultured cardiac myocyte gene expressions and signaling transduction cascades only to highlight their significance for pathological cardiac hypertrophy. Although cardiac myocytes express both AT₁ and AT₂ receptors (Booz and Baker, 1996), almost all of the biological responses to Ang II reported so far are mediated by AT₁ receptor. The effects of Ang II, which we describe in this section, are apparently all mediated by this receptor. Accumulating evidence has established that Ang II causes hypertrophy of neonatal cardiac myocytes (Baker and Aceto, 1990; Baker et al., 1992; Sadoshima and Izumo, 1993, 1997) and adult myocytes (Wada et al., 1996; Liu et al., 1998; Ritchie et al., 1998). Ang II directly induced the fetal phenotype of gene expressions, such as those of -MHC, skeletal -actin, and ANF, in neonatal rat cardiac myocytes, indicating the direct involvement of AT₁ receptor in cardiac gene reprogramming in vitro (Sadoshima and Izumo, 1993). Furthermore, Ang II stimulated the expression of immediate-early genes, including c-fos, c-jun, jun B, Egr-1, and c-myc (Sadoshima and Izumo, 1993). However, it is unclear whether the induction of these immediate-early genes is necessary for myocyte hypertrophy or gene reprogramming by Ang II, and the significance of induction of these immediate-early genes in hypertrophy remains to be determined.

Interestingly, Ang II, via AT₁ receptor, activates a diversity of intracellular signaling cascades in neonatal rat cardiac myocytes, although the role of these signaling cascades in myocyte hypertrophy or gene reprogramming remains to be elucidated. Cardiac myocyte AT₁ receptor couples to a heterotrimeric G protein, G_q. As with other G protein-coupled receptors, Ang II stimulates phosphatidylinositol-specific phospholipase C (PLC)- isoform through G_q, and the activation of PLC causes increases in inositol triphosphate and diacylglycerol, which in turn lead to an increase in release of Ca²⁺ from intracellular stores and activation of protein kinase C (PKC), respectively. Besides the above-mentioned basic cascades via G_q, it has been reported that Ang II in neonatal rat cardiac myocytes activates tyrosine kinases (Sadoshima et al., 1995), extracellular signal-regulated kinases (ERKs), c-Jun amino-terminal kinases (JNKs; Kudoh et al., 1997), 70-kDa ribosomal S6 kinase (p70S6K; Takano et al., 1996), 90-kDa ribosomal S6 kinase (p90RSK; Sadoshima and Izumo, 1995), p2lras, and phospholipases A₂ and D and increases phosphatidic acid and arachidonic acid, as mentioned in a previous review (Sadoshima and Izumo, 1997). Although AT₁ receptor has no intrinsic tyrosine kinase activity, the addition of Ang II (10⁷ M) to neonatal rat cardiac myocytes induced rapid phosphorylation of Janus kinase 2, Tyk2, signal transducer and activator of transcription (STAT)₁ and STAT₂ in the early stage up to 30 min, and phosphorylated STAT₃ in the late stage at 120 min (Kodama et al., 1998), although the significance of these observations is unknown. Ang II (10⁷ M) activated RhoA, which is responsible for Ang II-induced sarcomeric actin organization and ANF expression (Aoki et al., 1998). However, it remains unclear whether Ang II can indeed simultaneously activate all of the above-mentioned signaling cascades in myocytes. Furthermore, it remains to be determined to what extent each signaling cascade is involved in Ang II-induced cardiac myocyte hypertrophy and gene reprogramming seen in pathological cardiac hypertrophy in vivo.

We emphasize that despite abundant evidence for the activation of multiple signaling cascades by Ang II, the molecular mechanism of hypertrophy of cultured neonatal rat myocytes by Ang II is poorly understood. Ang II (10⁶ M) activated p70S6K in myocytes, and inhibition of this activation by rapamycin (0.5 ng/ml), an immunosuppressant, abolished the Ang II-induced increase in protein synthesis, without blocking ERK activation or c-fos mRNA induction, confirming the contribution of p70S6K to Ang II-induced hypertrophy (Takano et al., 1996). However, p70S6 kinase was not involved in Ang II-induced myocyte gene reprogramming, as shown by the lack of effect of rapamycin on Ang II-induced skeletal -actin, -MHC, or ANF expression (Sadoshima and Izumo, 1995). Notably, no information is available on the role of ERK activation in Ang II-induced myocyte hypertrophy or gene expression, although ERK activation is thought to be important for myocyte hypertrophy in response to other hypertrophic stimuli, such as phenylephrine (Force et al., 1996; Glennon et al., 1996; Sugden and Clerk, 1998a). Ang II (100 nM) induced the generation of reactive oxygen intermediates in neonatal rat cardiac myocytes, and the antioxidant, butylated hydroxyanisole (10 µM), significantly inhibited Ang II-induced myocyte enlargement and increased ³H-leucine incorporation, suggesting an important role of reactive oxygen intermediates in Ang II-induced myocyte hypertrophy (Nakamura et al., 1998). Ang II also stimulated endothelin-1 production in neonatal rat myocytes by activating PKC, which is involved in Ang II-induced myocyte hypertrophy via an autocrine mechanism (Ito et al., 1993).

C. Neonatal versus Adult Cardiac Myocytes

So far, most studies on the effects of Ang II on cardiac myocytes have been carried out using cultured neonatal rat cardiac myocytes. These cells have the ability to divide with serum stimulation, whereas adult rat cardiac myocytes are terminally differentiated and have no ability to divide, indicating a significant difference in phenotype between neonatal and adult cardiac myocytes. In fact, Schunkert et al. (1995) showed that the Ang II-induced increase in protein synthesis of isolated perfused adult rat heart was not accompanied by induction of c-fos and c-jun expression, in contrast to the situation in neonatal myocytes. Stretching of neonatal rat cardiac myocytes, the most popular in vitro model for investigation of the effect of load on cardiac myocytes, causes myocyte hypertrophy and gene reprogramming (Sadoshima and Izumo, 1997). It has been reported that Ang II secreted from myocytes plays a central role in stretch-induced hypertrophy, functioning as an autocrine in the neonatal rat myocyte culture system (Sadoshima et al., 1993). On the other hand, recent studies using isolated perfused adult rat heart preparation (Thienelt et al., 1997) or isolated perfused adult feline heart (Kent and McDermott, 1996) showed that increases in protein synthesis or c-fos and c-myc mRNA in the heart that were induced by systolic pressure overload were not prevented by an AT₁ receptor antagonist, which does not support a role for AT₁ receptor in pressure-induced acute growth responses in the adult heart. Thus, the data appear to be inconsistent for neonatal versus adult myocytes regarding the molecular mechanism of Ang II-induced hypertrophic response. The findings for neonatal myocytes should be interpreted with caution.

D. Cultured Cardiac Fibroblasts

The heart is composed of not only cardiac myocytes but also nonmyocyte cells, particularly fibroblasts. Unlike cardiac myocytes, cardiac fibroblasts can proliferate even in the adult heart. Furthermore, cardiac fibroblasts play a major role in the production of ECM proteins such as fibronectin and collagen (Dostal et al., 1996). Therefore, fibroblasts are critical for the development of cardiac fibrosis. Neonatal rat cardiac fibroblasts possess abundant AT₁ receptors. On the other hand, AT₂ receptors were undetectable in neonatal or adult rat cardiac fibroblasts (Villarreal et al., 1993; Crabos et al., 1994), indicating that the responses of cardiac fibroblasts to Ang II are due to AT₁ receptor. Unlike the situation with neonatal myocytes, Ang II treatment stimulated the proliferation of neonatal rat cardiac fibroblasts, as shown by significant increases in [³H]phenylalanine incorporation, [³H]thymidine uptake, and cell number (Schorb et al., 1993). These mitogenic effects of Ang II were completely blocked by losartan but not by PD123319, demonstrating the primary role of AT₁ receptor in Ang II-induced cardiac fibroblast proliferation. Ang II also exerted mitogenic effects on adult cardiac fibroblasts (Crabos et al., 1994). As in the case of neonatal cardiac myocytes, Ang II increased mRNA levels for c-fos, c-jun, jun B, Egr-1, and c-myc in cardiac fibroblasts via AT₁ receptor (Sadoshima and Izumo, 1993). Furthermore, Ang II increased collagen type I mRNA and the synthesis and secretion of collagen (Crabos et al., 1994), as well as mRNA expression and protein secretion of transforming growth factor-1 (TGF-1; Campbell and Katwa, 1997) and fibronectin (Iwami et al., 1996). Ang II also increased cardiac fibroblast osteopontin expression, and stimulation of cardiac fibroblast DNA synthesis by Ang II was completely blocked by antibodies against osteopontin and 3 integrin, suggesting that Ang II-induced cardiac fibroblast proliferation may require osteopontin engagement of 3 integrin (Ashizawa et al., 1996).

AT₁ receptor in cardiac fibroblasts couples to G_i, in contrast to AT₁ receptor in cardiac myocytes, which couples to G_q. Ang II signaling cascades differ significantly between cardiac fibroblasts and myocytes (Zou et al., 1998). Ang II (10⁶ M) activated the STAT signaling pathway as shown by gel mobility shift assay (Bhat et al., 1994). Immunoblot analysis showed that Ang II induced tyrosine phosphorylation of ERK, focal adhesion kinase, and Shc in neonatal rat cardiac fibroblasts, which was mediated not by PKC, as shown by the lack of inhibition with phorbol ester-sensitive PKC down-regulation, but rather by a G_i protein as shown by partial inhibition with pertussis toxin pretreatment (100 ng/ml; Schorb et al., 1994). Ang II (10⁶ M) activated ERK, and pretreatment with the specific MAP kinase kinase (MEK) inhibitor PD98059 (5 × 10⁵ M) completely blocked the Ang II-induced increase in thymidine incorporation, suggesting that Ang II-induced DNA synthesis in cardiac fibroblasts is mediated by MEK and, probably, ERK (Zou et al., 1998). However, the signaling cascade underlying the production of ECM proteins in cardiac fibroblasts by Ang II remains unclear.

E. Effects of In Vivo Angiotensin II Infusion on Heart

Figure 2 illustrates the cardiac molecular and cellular effects of Ang II in vivo. Ang II infusion in rats can induce cardiac hypertrophy via AT₁ receptor, independent of its blood pressure-elevating effect (Dostal and Baker, 1992). Furthermore, continuous infusion of Ang II (200 ng/min i.p.) in adult rats, while causing a moderate increase in blood pressure, produced both myocyte necrosis and myocytolysis, as shown by labeling of cardiac myocytes with exogenously administered monoclonal anti-myosin antibody; this subsequently caused cardiac fibroblast proliferation and resulted in significant scar formation, indicating the cardiotoxic effects of Ang II in vivo (Tan et al., 1991). Ang II (200 ng/kg/min s.c.) infusion in rats caused a small and gradual increase in blood pressure; elevated left ventricular mRNAs for skeletal -actin, -MHC, ANF, and fibronectin, preceding an increase in left ventricular mass; and elevated TGF-1 and types I and III collagen mRNA levels (Kim et al., 1995c); these increases were completely inhibited by candesartan cilexetil (3 mg/kg/day p.o.) but not by hydralazine (10 mg/kg/day). Thus, Ang II in vivo, via AT₁ receptor, directly induces cardiac myocyte hypertrophy and gene reprogramming, and probably fibroblast proliferation and subsequent fibrosis as well, independent of the elevation of blood pressure (Fig. 2), indicating the key role of Ang II in the development of pathological cardiac hypertrophy.

View larger version (24K): [in this window] [in a new window]   Fig. 2.   Proposed mechanism of AT1 receptor-mediated pathological cardiac hypertrophy. Ang II induces cellular hypertrophy, gene reprogramming or necrosis in cardiac myocytes, and cellular proliferation and up-regulation of fibrosis-associated genes in cardiac fibroblasts, which are all mediated via AT1 receptor.

Investigations of the in vivo effects of Ang II on cardiac intracellular signaling cascades are essential to elucidate the molecular mechanism underlying Ang II-induced pathological cardiac hypertrophy. In contrast to the detailed in vitro studies on cultured myocytes and fibroblasts described above, the action of Ang II on cardiac signaling cascades in vivo is poorly understood. Accumulating in vitro evidence on cultured cardiac myocytes or fibroblasts suggests that MAP kinases, including ERK or JNK, may be responsible for myocyte hypertrophy and gene reprogramming or fibroblast proliferation (Force et al., 1996; Sugden and Clerk, 1998b; Wang et al., 1998). Recent work on the effects of Ang II infusion in vivo in conscious rats showed that Ang II-induced cardiac activation of JNK occurs in a more sensitive manner than that of ERK, and JNK activation by Ang II without ERK activation is followed by activation of activator protein-1 (AP-1; composed of c-Fos and c-Jun proteins) (Yano et al., 1998). Importantly, AP-1 regulates the expression of various genes by binding the AP-1 consensus sequence present in their promoter regions. Interestingly, fetal phenotypes of cardiac genes such as skeletal -actin and ANF (Karin, 1995; Force et al., 1996), and cardiac fibrosis-associated genes such as TGF-1 (Kim et al., 1989) and collagen type I (Katai et al., 1992) have AP-1 responsive sequences in their promoter regions. Indeed, AP-1 activation has been demonstrated to lead to increased promoter activity of skeletal -actin (Bishopric et al., 1992) and TGF-1 (Kim et al., 1990). Therefore, it is intriguing to postulate that JNK activation, in part through activation of AP-1, may be implicated in Ang II-induced cardiac hypertrophic response in vivo (Fig. 3). Thus, important differences in the molecular mechanism of Ang II-induced cardiac hypertrophy exist between the adult heart in vivo and neonatal cardiac myocytes in vitro. However, it remains unclear whether the increased MAP kinase induced by Ang II infusion originates in myocytes, fibroblasts, or both. Further detailed work is needed to demonstrate whether activation of JNK/AP-1 by Ang II infusion is responsible for the above-mentioned cardiac hypertrophy-associated gene expressions.

View larger version (12K): [in this window] [in a new window]   Fig. 3.   Proposed in vivo molecular mechanism of cardiac hypertrophy and remodeling-associated gene expressions via AT1 receptor. Ang II in vivo activates cardiac JNK more potently than ERK, and JNK activation is postulated to induce the activation of AP-1, leading to target gene expressions. TRE, TPA-responsive element.

Ang II, via AT₁ receptor, is known to facilitate the release of norepinephrine from cardiac sympathetic nerve terminals (Zimmerman, 1981; Rump et al., 1994). In situ and in vitro studies in dogs have demonstrated that Ang II enhances cardiac myocyte function via AT₁ receptor present in intrinsic adrenergic neurons (Horackova and Armour, 1997). In Ang II-infused rats, surgical cardiac sympathectomy or treatment with atenolol, a ₁-adrenergic receptor blocker, significantly prevented cardiac myocyte necrosis, showing that Ang II-induced cardiac damage is at least in part mediated by catecholamine release from cardiac sympathetic neurons (Henegar et al., 1998). Thus, the activation of cardiac sympathetic neurons by Ang II also contributes to pathological cardiac hypertrophy.

F. Effects of Angiotensin Blockade on Experimental Cardiac Diseases

1. Spontaneously Hypertensive Rats and Other Hypertensive Models. As shown in Table 1, molecular phenotypes of pathological cardiac hypertrophy differ among various types of cardiac diseases. In spontaneously hypertensive rats (SHR), the most popular model of human essential hypertension, left ventricular mRNAs for skeletal -actin, ANF, and collagen types I and III were higher and -MHC mRNA levels were lower than those in normotensive control Wistar-Kyoto rats (WKY; Ohta et al., 1996a). Thus, SHR exhibited not only cardiac hypertrophy but also cardiac gene reprogramming. As shown in Table 2, an AT₁ receptor antagonist (SC-52458) or an ACE inhibitor (imidapril) with a mildly hypotensive effect (~30 mm Hg) attenuated the increases in cardiac ANF and collagen types I and III mRNAs and significantly normalized the decreased -MHC mRNA. On the other hand, a calcium channel blocker or an ₁-adrenergic blocker had no effect on these mRNA expressions in SHR, despite blood pressure-lowering effects comparable with those of SC-52458 and imidapril. These observations show that cardiac gene reprogramming in SHR can be attributed at least in part to direct AT₁ receptor activation by Ang II. Furthermore, the combination of doxazosin with atenolol suppressed cardiac collagen types I and III expressions, indicating that the enhanced collagen expression was also in part mediated by -adrenergic receptor (Table 2; Ohta et al., 1996a). Treatment of SHR with M17055, a diuretic, normalized only cardiac collagen type III (Kim et al., 1996a).

View this table: [in this window] [in a new window]   TABLE 1 Differential molecular phenotypes among various rat cardiac disease models

View this table: [in this window] [in a new window]   TABLE 2 Effects of various antihypertensive drugs on left ventricular gene expressions in SHR

TGR(mRen2)27, a transgenic hypertensive rat strain carrying the murine Ren-2 gene, is characterized by a lack of increase in plasma and renal renin concentrations and a high adrenal renin concentration, as in the case of SHR (Mullins et al., 1990). Ren-2 transgene was shown to be expressed in the cardiac tissue of TGR(mRen2)27 (Lee et al., 1995). Interestingly, the pattern of altered cardiac gene expression in TGR(mRen2)27 was similar to that in SHR, as mentioned. As shown by a comparison of the effects of an AT₁ receptor antagonist (candesartan cilexetil) with those of a calcium channel blocker (manidipine), a -adrenergic blocker (atenolol), and an -adrenergic blocker (doxazosin), the cardiac AT₁ receptor, but not high blood pressure, was involved in cardiac hypertrophy and gene reprogramming in TGR(mRen2)27, and the cardiac renin-angiotensin system via AT₁ receptor may be involved in cardiac hypertrophy and gene expressions in this transgenic rat (Ohta et al., 1996b). Therefore, this appears to be a useful model for study of the role of the cardiac renin-angiotensin system in cardiac disease.

As shown in Table 1, stroke-prone SHR (SHRSP), a substrain of SHR that is regarded as a primary model of human malignant hypertension, showed a different cardiac molecular phenotype from SHR or TGR(mRen2)27, as shown by increased expressions of -MHC and TGF-1 mRNAs (Kim et al., 1995b, 1996b). Losartan (30 mg/kg/day) induced regression of left ventricular hypertrophy in SHRSP and normalized the altered cardiac expressions of -MHC, skeletal -actin, ANF, TGF-1, and collagen types I and III in SHRSP to a greater extent than amlodipine (5 mg/kg/day) despite comparable hypotensive effects (Kim et al., 1996b). However, the increase in -MHC mRNA levels in SHRSP was not significantly inhibited by losartan or amlodipine. Thus, up-regulation of -MHC mRNA in SHRSP seems to be due to neither Ang II nor hypertension, although the mechanism remains unknown. Left ventricular ERK and JNK activities were chronically higher in SHRSP than in WKY (Izumi et al., 1998). Treatment of SHRSP with losartan (30 or 50 mg/kg/day) significantly inhibited the increase in left ventricular JNK activity, along with the regression of left ventricular hypertrophy, and did not lower cardiac ERK activity. Furthermore, hydralazine (50 mg/kg/day) treatment, which completely normalized blood pressure, caused neither significant regression of cardiac hypertrophy nor decreased cardiac JNK or ERK activity. Thus, the increased cardiac JNK activity in SHRSP is at least in part directly mediated by AT₁ receptor and JNK may contribute to pathological cardiac hypertrophy in SHRSP. Further research on JNK may provide new insights into the in vivo molecular mechanism of Ang II-mediated pathological cardiac hypertrophy.

2. Acute Pressure Overload Model. So far, acute pressure overload, produced by aortic banding or coarctation, has been the most popular model for study of the mechanism of cardiac hypertrophy in vivo. This model is characterized by acute cardiac hypertrophy induced by rapid and severe pressure overload to the heart, in contrast to the above-mentioned slow and mild development of cardiac hypertrophy in hypertensive rats such as SHR or SHRSP. Therefore, it should be noted that this model is rather artificial and may not be a suitable physiological model of human cardiac hypertrophy, which develops slowly and chronically over the long term. Acute pressure overload in rats due to aortic banding rapidly caused left ventricular increases in mRNAs for -MHC, skeletal -actin, ANF, TGF-1, and collagen types I and III and a reciprocal decrease in -MHC mRNA (Table 1; Parker and Schneider, 1991; Villarreal and Dillmann, 1992; Parker, 1995). In this model, as in SHRSP, the decrease in left ventricular -MHC mRNA occurred earlier than the increase in -MHC mRNA . Treatment with losartan (10 mg/kg/day) suppressed left ventricular hypertrophy and ANF and TGF-1 up-regulation after aortic coarctation, suggesting that AT₁ receptor may participate in cardiac hypertrophy and ANF and TGF-1 up-regulation in this model (Everett et al., 1994). However, the effects of losartan on genes other than ANF and TGF-1 were not examined in this study. Acute pressure overload, produced by abdominal aortic constriction in rats, caused tyrosine phosphorylation of left ventricular JAK1, JAK2, Tyk2, STAT₁, STAT₂, and STAT₃, whereas treatment with an AT₁ receptor antagonist (30 mg/kg/day E4177) or an ACE inhibitor (10 mg/kg/day cilazapril) suppressed tyrosine phosphorylation of Tyk2 completely and that of JAK2 partially but failed to inhibit JAK1 (Pan et al., 1997). Thus, cardiac AT₁ receptor may directly contribute to the activation of JAK2 and Tyk2 in acute pressure-overloaded rats. Recently, AT_1a receptor knockout mice were successfully developed (Sugaya et al., 1995), in which cardiac AT₁ receptor mRNA levels (probably due to AT_1b receptor) are less than 10% of those in wild-type mice (Harada et al., 1998a). In contrast to the contribution of AT₁ receptor to pressure overload-induced cardiac hypertrophy in adult rats, acute pressure overload by aortic constriction elicited significant activation of ERK and increased the expression of immediate-early genes and the fetal phenotype of genes such as -MHC and ANF, myocyte hypertrophy, and fibrosis in the heart of both AT_1a knockout and wild-type mice (Harada et al., 1998a,b). However, blockade of pressure overload cardiac hypertrophy in adult animals with an AT₁ receptor antagonist is not at all equivalent to the pressure overload model using AT₁ receptor knockout animals. It is possible that deletion of the AT_1a receptor gene from early embryogenesis promotes a compensatory ability to use pathways other than AT₁ receptor for cardiac hypertrophic response, which may explain the sufficient response to hypertrophic stimuli seen in knock-out mice as well as wild-type mice. Furthermore, the possible contribution of AT_1b receptor to cardiac hypertrophy in AT_1a receptor knockout mice cannot be excluded. Thus, the findings obtained using this model should be interpreted with cautious.

3. Myocardial Infarction. Myocardial infarction is the most common cause of heart failure. Clinically, ACE inhibitors have proved effective in reducing death and complications, improving symptomatic status, and attenuating the progressive nature of cardiac failure in symptomatic patients with ventricular diastolic and/or systolic dysfunction (The CONSENSUS Trial Study Group, 1987; The SOLVD Investigators, 1991). AT₁ receptor antagonists had beneficial effects similar to those of ACE inhibitors on cardiac dysfunction, hypertrophy, and fibrosis after myocardial infarction in the rat (Schieffer et al., 1994; Weber, 1997). Interestingly, as shown in Table 1, the molecular phenotype in nonischemic left ventricular myocardium of myocardial infarcted rats differed from that of hypertensive or acute pressure-overloaded models, as shown by the lack of change in -MHC mRNA (Hanatani et al., 1995; Yoshiyama et al., 1999). An AT₁ receptor antagonist (1 and 10 mg/kg/day candesartan cilexetil) and an ACE inhibitor (1 and 10 mg/kg/day imidapril) significantly and similarly suppressed cardiac hypertrophy and the increased mRNA expressions of -MHC, ANP, and skeletal -actin in nonischemic left ventricular myocardium at 1 and 4 weeks and collagen types I and III mRNA up-regulation at 4 weeks after coronary arterial ligation (Yoshiyama et al., 1999). Furthermore, these molecular effects of candesartan cilexetil and imidapril were associated with improvements in cardiac systolic and diastolic dysfunction, as assessed with Doppler echocardiography. These findings support the notion that normalization of the molecular phenotype in the nonischemic left ventricle after myocardial infarction may be linked to improvement of cardiac dysfunction. Furthermore, unlike the situation in SHRSP, up-regulation of -MHC in the left ventricle with myocardial infarction seems to be mediated by AT₁ receptor.

4. Volume Overload Model. Previous work on the effects of AT₁ receptor antagonist (40 mg/kg/day losartan) treatment on rat cardiac hypertrophy due to aortocaval shunt showed the contribution of AT₁ receptor to the development of cardiac hypertrophy and dysfunction in the volume overload model (Ruzicka et al., 1994b). As shown in Table 1, the molecular phenotype in cardiac volume overload was characterized only by increases in left ventricular ANF and collagen type III mRNAs, indicating that the volume-overloaded heart has a very unique molecular phenotype (Kim et al., 1997b). The lack of increase in collagen type I and TGF-1 expressions may explain why volume overload due to aortocaval shunt does not increase cardiac collagen accumulation (Ruzicka et al., 1994a), in contrast to the increased collagen accumulation seen in other hypertrophic models, such as hypertension, acute pressure overload, or myocardial infarction. Treatment with an AT₁ receptor antagonist (10 mg/kg/day CS-866) or an ACE inhibitor (10 mg/kg/day temocapril) for 7 days decreased left ventricular mass and ANF and collagen type III mRNAs in this model (Kim et al., 1997b). Together with the lack of change in plasma renin activity or aldosterone in this model, these findings suggest that cardiac AT₁ receptor is at least partly involved in not only cardiac hypertrophy but also altered gene expression caused by volume overload.

5. Diabetes. Clinical data show that myocardial dysfunction frequently occurs in patients with diabetes mellitus (DM), even in the absence of coronary artery disease, supporting the concept of primary diabetic cardiomyopathy (Regan et al., 1977; Mahgoub and Abd-Elfattah, 1998). Furthermore, abnormalities in cardiac function, including decreased cardiac contractility, are reported to occur in streptozotocin-induced diabetic animals (Feuvray et al., 1979; Litwin et al., 1990). However, the mechanism responsible for cardiomyopathy in DM, particularly NIDDM, is poorly understood. Sechi et al. (1994) found that hyperglycemia leads to increases in cardiac AT₁ receptor density and mRNA levels without altering plasma renin concentrations, suggesting possible activation of the cardiac renin-angiotensin system in diabetic rats. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a recently developed model of human NIDDM (Kawano et al., 1992), show a unique cardiac molecular phenotype (Table 1; Yagi et al., 1997). An AT₁ receptor antagonist (10 mg/kg/day E-4177) and an ACE inhibitor (1 and 10 mg/kg/day cilazapril) similarly prevented left ventricular up-regulation of TGF-1 mRNA and down-regulation of -MHC mRNA in OLETF rats, suggesting that AT₁ receptor may be involved in these gene expressions (Kim et al., 1997c).

	IV. Molecular and Cellular Actions of Angiotensin II in Blood Vessels

Top Previous Next References

A. Cultured Smooth Muscle Cells

Ang II has been established to stimulate protein synthesis and induce cellular hypertrophy in cultured vascular smooth muscle cells (SMCs) via AT₁ receptor (Geisterfer et al., 1988; Berk et al., 1989). Because the abnormal growth of vascular SMCs plays a major role in the development of various vascular diseases such as hypertension and atherosclerosis (Gibbons and Dzau, 1994), this article focuses on the signal transduction underlying Ang II-induced vascular SMC growth. Cultured vascular SMCs express AT₁ receptor but not AT₂ receptor. A growing body of evidence shows that AT₁ receptor activation in cultured vascular SMCs, coupled to the G protein G_q, causes not only activation of PLC- leading to increases in diacylglycerol and intracellular calcium but also activation of multiple signal transduction cascades. Many excellent reviews that focus on the mechanism of Ang II-activated signal transduction in vascular SMC have recently been published (Schieffer et al., 1996; Berk and Corson, 1997; Griendling et al., 1997; Bernstein et al., 1998).

Ang II treatment of cultured rat aortic SMCs caused activation of ERK (Duff et al., 1992; Tsuda et al., 1992), p70S6K (Giasson and Meloche, 1995), and p90RSK (Takahashi et al., 1997) and phosphorylation of multiple protein tyrosine residues (Molloy et al., 1993), including focal adhesion kinase (Polte et al., 1994), paxillin (Leduc and Meloche, 1995), PLC- (Marrero et al., 1994), JAK2, STAT₁ (Marrero et al., 1995), c-Src (Ishida et al., 1995), p130 CAS (Sayeski et al., 1998), and Pyk2. Furthermore, Ang II has recently been reported to activate JNK (Schmitz et al., 1998) and p38 (Kusuhara et al., 1998). However, little is known about the role of these signal cascades in Ang II-induced hypertrophic response. Treatment of rat aortic SMCs with two tyrosine kinase inhibitors, genistein and herbimycin A, completely abolished the stimulatory effect of Ang II (100 nM) on protein synthesis, without affecting Ang II-stimulated inositol triphosphate production, Ca²⁺ mobilization, ERK activation, or c-fos mRNA induction (Leduc et al., 1995). Thus, the tyrosine kinase pathway contributes to Ang II-induced cellular hypertrophy in rat aortic SMCs, independent of PLC activation, ERK activation, or c-fos induction. Rapamycin, an immunosuppressant drug that selectively blocks S6 kinase, significantly inhibited Ang II (100 nM)-induced protein synthesis as well as activation of p70S6K, without inhibiting activation of ERK or induction of c-fos mRNA (Giasson and Meloche, 1995). Thus, p70S6K plays a critical role in the hypertrophic response of vascular SMCs to Ang II. Without affecting p70S6 kinase activity, PLC activity, or protein tyrosine phosphorylation, a specific MEK inhibitor, PD98059 (30 µM), inhibited Ang II (100 nM)-induced protein synthesis in rat aortic SMCs by 70%, and PD98059 (30 µM) and rapamycin (10 ng/ml) exerted additive inhibitory effects on Ang II-induced protein synthesis, suggesting that activation of MEK and probably activation of ERK are obligatory steps for Ang II-induced hypertrophy in vascular SMCs, with a mechanism distinct from that of p70S6K (Servant et al., 1996). Ang II also promoted the activation of both NADH and NADPH oxidases in cultured rat aortic SMCs, associated with an increase in superoxide generation, whereas treatment with an NADPH oxidase inhibitor (10 µM diphenylene iodinium) or an NADH oxidase inhibitor (50 µM quinacrine) led to inhibition of both Ang II (100 nM)-induced protein synthesis and superoxide generation (Griendling et al., 1994). Thus, Ang II-induced superoxide generation seems to function as a second messenger implicated in cellular hypertrophy of vascular SMCs. Furthermore, Ang II induced tyrosine phosphorylation of epidermal growth factor (EGF) receptor and its association with Shc and Grb2 in rat aortic SMCs, whereas treatment with AG1478, a specific EGF receptor kinase inhibitor, inhibited Ang II-induced ERK activation and protein synthesis, supporting the notion that Ang II causes cellular hypertrophy, at least in part mediated by EGF receptor transactivation (Eguchi et al., 1998). Thus, tyrosine kinases, p70S6K, ERK, superoxide, or EGF receptor, via different mechanisms, may be responsible for Ang II-induced cellular hypertrophy in vascular SMCs. However, it remains unresolved whether these signal cascades are indeed all simultaneously activated by Ang II in vivo. Tyrosine phosphorylation of platelet-derived growth factor (PDGF) -receptor by Ang II in vascular SMCs has been also reported, although the role of transactivation of this receptor is unknown (Linseman et al., 1995).

Long-term treatment with Ang II can induce delayed mitogenic effects on cultured rat aortic SMCs, as shown by the observation that Ang II increased DNA synthesis 5- to 8-fold in vascular SMCs after 48 h, followed by an increase in cell number after 5 days (Weber et al., 1994a). This delayed mitogenic effect of Ang II could be inhibited by suramin, a compound shown to interfere with autocrine cell transformation, suggesting the involvement of suramin-sensitive autocrine growth factors in Ang II-induced delayed proliferation. Furthermore, Ang II-induced proliferation of vascular SMCs was suggested to be mediated by the autocrine action of PDGF or basic fibroblast growth factor (bFGF) released into the medium (Gibbons et al., 1992). In porcine coronary SMC, Ang II (10⁶ M) also induced cell proliferation after 96 h and activated phosphatidylinositol 3-kinase (PI3-kinase), a heterodimeric protein composed of 85- and 110-kDa subunits that catalyzes the synthesis of 3-phosphorylated phosphoinositides, whereas LY294002 (10⁵ to 10¹⁰ M), a specific inhibitor of PI3-kinase, inhibited the increases in both RNA and DNA synthesis as well as the increase in cell number generated by Ang II stimulation, supporting the important role of PI3-kinase in Ang II-induced vascular SMC proliferation (Saward and Zahradka, 1997).

Vascular diseases are triggered and developed by a variety of factors, such as growth factors, ECM proteins, cytokines, or chemokines. Accumulating evidence indicates that Ang II in vascular SMCs regulates various gene expressions implicated in vascular diseases. Ang II stimulated the induction of various growth factors, including TGF-1 mRNA and protein (Gibbons et al., 1992), PDGF mRNA (Naftilan et al., 1989), bFGF (Gibbons et al., 1992), vascular endothelial growth factor mRNA (VEGF; Williams et al., 1995), and insulin-like growth factor-I mRNA and protein (Delafontaine and Lou, 1993). Ang II-induced TGF-1 mRNA expression in vascular SMCs was mediated by activation of ERK and AP-1 (Hamaguchi et al., 1999). Ang II also stimulated induction of various kinds of ECM components, including fibronectin mRNA and protein (Tamura et al., 1998), collagen protein (Kato et al., 1991), laminin, and tenascin mRNA and protein (Sharifi et al., 1992). Ang II increased glucose transporter GLUT- I mRNA and activity in rat aortic SMCs (Low et al., 1992). Ang II stimulated mRNA expression and activity of plasminogen activator inhibitor (PAI)-1 and -2 in rat aortic SMCs, suggesting the involvement of Ang II in thrombosis (Feener et al., 1995). Ang II also stimulated the induction of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein in rat aortic SMCs, which was due to activation of tyrosine kinases and ERK or generation of superoxide, suggesting the participation of Ang II in monocyte infiltration into the vessel wall (Chen et al., 1998). It is intriguing that these factors may play an important role in Ang II-mediated vascular diseases in an autocrine or a paracrine manner.

B. Cultured Endothelial Cells

As in rat aortic SMCs, Ang II promoted PAI-1 and PAI-2 mRNA and protein expressions in rat microvessel endothelial cells isolated from epididymal fat pads via AT₁ receptor (Feener et al., 1995). Thus, AT₁ receptor in endothelial cells may regulate plasminogen activation. In coronary endothelial cells from explanted human heart, Ang II, via AT₁ receptor, induced concentration-dependent increases in E-selectin mRNA and protein and significantly increased leukocyte adhesion at wall shear stress. This adhesion to endothelial cells was due to E-selectin expression, as demonstrated by the inhibition of leukocyte adhesion with anti-E-selectin antibody (Grafe et al., 1997). Therefore, AT₁ receptor in endothelial cells may participate in leukocyte accumulation in the vessel wall, which is a hallmark of early atherosclerosis and plaque progression. Ang II has also been shown to induce expression of endothelin-1 mRNA and protein in bovine carotid arterial endothelial cells via AT₁ receptor (Imai et al., 1992). In bovine retinal microcapillary endothelial cells, Ang II alone had no effect on cell growth or tube formation, but Ang II in a dose-dependent manner induced significant increases in mRNA and protein for kinase domain-containing receptor/total liver kinase (KDR/Flk-1), which is a VEGF receptor, and significantly enhanced VEGF-induced cell proliferation and tube formation, mediated by AT₁ receptor (Otani et al., 1998). These findings suggest that AT₁ receptor may contribute to the development of diabetic retinopathy by enhancing VEGF-induced angiogenic activity.

C. Effects of In Vivo Angiotensin II Infusion on Vascular Tissues

Several in vivo experiments have shown that Ang II can induce vascular SMC proliferation in vivo (Daemen et al., 1991; Griffin et al., 1991; Simon and Altman, 1992; Su et al., 1998). Interestingly, Ang II infusion (200 ng/min i.p.) in rats subjected to balloon injury 2 weeks earlier showed that the proliferative influence of Ang II is more remarkable in neointimal SMCs than in SMCs of the underlying media or of the normal vessel wall, indicating that the proliferative activity of Ang II in vivo depends on the preexisting proliferative status of vascular SMCs (Daemen et al., 1991). Ang II infusion (200 ng/kg/min s.c. for 10-12 days) in rats increased mesenteric vascular media width, media cross-sectional area, and media/lumen ratio, and these changes were not inhibited by treatment with hydralazine despite normalization of blood pressure, indicating that Ang II caused vascular growth in vivo at least in part in a direct manner (Griffin et al., 1991).

Despite detailed investigations into the molecular mechanism of Ang II-mediated vascular SMC growth in vitro, this process is poorly understood. Ang II infusion, at least in part independent of its blood pressure-elevating effect, increased aortic mRNA and protein expression of fibronectin, which is an ECM protein that induces phenotypic change of vascular SMCs from a contractile to a synthetic phenotype (Kim et al., 1994a). bFGF may play a key role in Ang II-mediated vascular SMC replication in vivo, as shown by the observation that i.v. injection of anti-bFGF antibody significantly inhibited the mitogenic effect of Ang II infusion on rat carotid arteries (Su et al., 1998). Ang II (0.7 mg/kg/day) infusion in rats doubled superoxide production in rat aorta (mainly media) by activation of NADH/NADPH oxidase, which was completely blocked by treatment with losartan (25 mg/kg/day; Rajagopalan et al., 1996; Laursen et al., 1997). On the other hand, norepinephrine (2.8 mg/kg/day) infusion did not increase vascular superoxide production, despite a hypertensive effect comparable with that of Ang II, suggesting that SMC growth due to Ang II may be specifically mediated by increased superoxide generation. Ang II infusion (0.7 mg/kg/day s.c.) in rats increased heme oxygenase-1 (HO-1) mRNA and protein in the endothelium and adventitia of the aorta, which was prevented by treatment with losartan (25 mg/kg/day; Ishizaka et al., 1997). Because HO-1 is an oxidant-sensitive gene, it is possible that increased oxidative stress is a trigger for HO-1 mRNA up-regulation in Ang II-infused rat aorta and that HO-1 may serve to abrogate this increased stress caused by Ang II. Ang II infusion (0.75 mg/kg/day s.c.) stimulated aortic thrombin receptor mRNA expression in rats, which was blocked by either losartan or heparin-binding chimera of human Cu/Zn superoxide dismutase but not by normalization of blood pressure with hydralazine treatment, suggesting that Ang II increases vascular thrombin receptor by AT₁ receptor-mediated superoxide production and may be implicated in the pathophysiology of atherosclerosis by thrombin cascade activation (Capers et al., 1997). The i.p. injection of Ang II (10⁷ M once daily for 2 days) in mice resulted in increased oxidized low-density lipoprotein (LDL) uptake by peritoneal macrophages and increased macrophage proteoglycan content, suggesting that Ang II may accelerate atherosclerosis by promoting foam cell formation and cholesterol accumulation in the vascular wall (Keidar and Attias, 1997).

D. Effects of Angiotensin Blockade on Experimental Vascular Diseases

1. Hypertensive Rats. Table 3 summarizes the in vivo molecular effects of AT₁ receptor antagonists on various rat vascular diseases. Accumulating evidence indicates that TGF-1 and various ECM proteins are responsible for the development of vascular remodeling. Aortic TGF-1, fibronectin, and collagen type IV mRNA levels are higher in SHR than in WKY, and all of these elevated mRNAs in the aorta of SHR were significantly reduced by an ACE inhibitor, alacepril (50 mg/kg/day), or an AT₁ receptor antagonist, SC-52458 (50 mg/kg/day; Ohta et al., 1994). In the mesenteric artery and aorta of SHRSP, the increases in mRNA levels for TGF-1; fibronectin; collagen types I, III, and IV; and laminin were suppressed by candesartan (1 and 10 mg/kg) or enalapril (10 mg/kg; Kim et al., 1995b). Importantly, these effects were associated with the suppression of medial hypertrophy of the aorta and mesenteric artery of SHRSP, suggesting that AT₁ receptor may be responsible for vascular thickening via stimulation of TGF-1 and ECM protein expressions.

View this table: [in this window] [in a new window]   TABLE 3 In vivo molecular effects of AT1 receptor antagonists on various rat vascular disease models

Aortic ERK and JNK activities are significantly increased with the development of hypertension, and in particular, aortic ERK activity is gradually and chronically enhanced in the development of hypertension and is associated with an increase in aortic weight (Kim et al., 1997a). Unlike the case in vascular tissue, there was no significant increase in ERK or JNK activity in other tissues such as liver, stomach, spleen, or lung of hypertensive rats. A previous report showed no increase in vascular PKC activity in hypertensive rats (Silver et al., 1992). Thus, the increase in vascular MAP kinase activity seems to be a specific event, rather than nonspecific, in hypertensive rats. Furthermore, losartan (30 and 50 mg/kg/day) significantly decreased aortic ERK activity in SHRSP to a greater extent than nifedipine (45 mg/kg/day), although both drugs caused similar hypotensive effects (Hamaguchi et al., 1999). These findings raise the possibility that increased aortic ERK activity in hypertensive rats may be due in part to AT₁ receptor and may be implicated in vascular remodeling that accompanies hypertension.

2. Balloon Injury. Arterial injury produced by balloon angioplasty causes proliferation and migration of medial smooth muscle cells, leading to progressive neointimal thickening and narrowing of the vascular lumen (Gibbons and Dzau, 1994). This arterial repair process has been shown to be associated with significant induction of various kinds of genes, including immediate-early genes (Miano et al., 1990), growth factors, and ECM components (Majesky et al., 1990), suggesting the importance of these genes in the formation of neointima. Ang II, via AT₁ receptor, is responsible for neointima formation in rat artery after balloon injury (Powell et al., 1989; Prescott et al., 1991). As shown in Table 3, candesartan cilexetil (10 mg/kg/day) significantly inhibited induction of c-fos, c-jun, and Egr-1 mRNAs after balloon injury and significantly inhibited fibronectin mRNA, suggesting that inhibition of fibronectin expression by AT₁ receptor antagonist may be in part responsible for inhibition of vascular smooth muscle cell proliferation and/or migration (Kim et al., 1995a). Furthermore, arterial JNK and ERK activities were rapidly and transiently increased with peaks at 5 min (Kim et al., 1998). Treatment with AT₁ receptor antagonist (20 mg/kg/day E4177) significantly inhibited the activation of JNK and ERK in injured artery, demonstrating that Ang II, via AT₁ receptor, is responsible for balloon injury-induced arterial JNK and ERK activations (Fig. 4). Notably, inhibition of JNK activation by AT₁ receptor antagonist was greater than 80%, whereas that of ERK activation was about 40%, suggesting that JNK activation may be due more to AT₁ receptor than ERK activation. Furthermore, after activation of JNK and ERK, transcription factor AP-1 complex, composed of c-Fos and c-Jun proteins, was activated with a peak at 3 h after injury, and this was blocked 47% by E4177 (Fig. 5). These findings support the notion that AT₁ receptor seems to participate in neointima formation after balloon injury, probably mediated by activation of JNK or ERK followed by AP-1 activation. The inhibition of neointima in balloon-injured artery by AT₁ receptor antagonist also may be in part due to suppression of PDGF receptor activation, as shown by the findings that PDGF receptor tyrosine phosphorylation was enhanced in injured artery and was suppressed by candesartan cilexetil (10 mg/kg/day) but not by amlodipine (10 mg/kg/day; Abe et al., 1997).

View larger version (24K): [in this window] [in a new window]   Fig. 4.   Inhibition of arterial ERK (A) and JNK (B) in rat balloon-injured artery by E4177 (20 mg/kg/day) and cilazapril (10 mg/kg/day). Top panels indicate representative autoradiograms of ERK or JNK activities. non-inj, noninjured control carotid artery; Ve, balloon-injured artery treated with vehicle; E4177, balloon-injured artery treated with E4177; Cila, balloon-injured artery treated with cilazapril. Values are mean ± S.E. *P< .01 versus Ve.

View larger version (38K): [in this window] [in a new window]   Fig. 5.   Time course of activation of AP-1 in rat balloon-injured artery (A) and its inhibition by E4177 (20 mg/kg/day) and cilazapril (10 mg/kg/day) (B). Ve, balloon-injured artery of rats treated with vehicle; Cila, balloon-injured artery of rats treated with cilazapril; E4177, balloon-injured artery of rats treated with E4177; NS, nonspecific binding; F, free probe. Values are mean ± S.E.

Unlike in the balloon-injured rat carotid artery model, Ang II may not play a role in the development of neointimal thickening in the pig (Huckle et al., 1996) or baboon (Hanson et al., 1991). Furthermore, human trials of the effects of cilazapril (an ACE inhibitor) on restenosis yielded negative results (The MERCATOR Study Group, 1992). There may be species differences in the role of Ang II in neointimal hyperplasia, and it remains unclear whether Ang II contributes to the development of restenosis in humans.

3. Other Models. ACE inhibitors have been reported to exert potent antiatherosclerotic actions in Watanabe heritable hyperlipidemic rabbits (Chobanian et al., 1990) and high-cholesterol-fed rabbits (Schuh et al., 1993). In the latter model, treatment with an AT₁ receptor antagonist (20 mg/kg/day E4177) as well as an ACE inhibitor (10 mg/kg/day enalapril) for 5 weeks reduced aortic cholesterol content (Sugano et al., 1996), whereas an other study showed that treatment with an AT₁ receptor antagonist (30 mg/kg/day SC-51316 p.o.) for 3 months did not significantly attenuate aortic atherosclerosis (Schuh et al., 1993). Thus, the role of AT₁ receptor in hyperlipidemic atherosclerosis in rabbits is controversial. However, recent work showed that AT₁ receptor mRNA expression and binding were significantly increased mainly in the media and to some extent in the intima of atherosclerotic aorta from high-cholesterol-fed rabbits (Yang et al., 1998). Furthermore, without affecting plasma cholesterol levels, losartan (25 mg/kg/day for 3 months) in apolipoprotein E-deficient mice with severe hypercholesterolemia and extensive atherosclerosis increased the resistance of LDL to CuSO₄-induced oxidative modification, and this was associated with a reduction in atherosclerotic lesion area by 80% (Keidar et al., 1997). Thus, AT₁ receptor antagonists may have beneficial effects on atherosclerosis due to inhibition of LDL lipid peroxidation. DM is also an important risk factor for atherosclerosis. Cilazapril (1 and 10 mg/kg/day) and E4177 (10 mg/kg/day) prevented wall thickening and increased perivascular fibrosis in arterioles and small coronary arteries of OLETF rats, suggesting an important role of AT₁ receptor in diabetic vascular disease (Kim et al., 1997c). However, the molecular mechanism underlying the contribution of AT₁ receptor to diabetic vascular lesions remains to be elucidated.

	V. Molecular and Cellular Actions of Angiotensin II in Kidney

Top Previous Next References

A. Cultured Glomerular Cells

Glomerular diseases are mainly caused by glomerular hypertension, DM, or inflammation and are commonly characterized by mesangial cell overgrowth and excessive accumulation of ECM proteins. The development of such glomerular injuries is largely responsible for glomerular capillary obliteration and decline in the glomerular filtration rate (GFR), ultimately leading to renal failure, as reviewed elsewhere (Wesson, 1998). Thus, glomerular diseases are the most clinically important kidney diseases. Accumulating evidence suggests that mesangial cells, which are a major determinant in regulation of GFR, play a key role in progression from glomerular injury to glomerulosclerosis, due to their overgrowth and synthesis of excess ECM proteins. Therefore, in this review, we focus on the molecular effects of Ang II on glomerular mesangial cells.

Interestingly, Ang II concentrations within the kidney are ~1000-fold higher than those in circulating blood, suggesting the presence of an intrarenal renin-angiotensin system (Seikaly et al., 1990; Ingelfinger and Dzau, 1991). Ang II plays a critical role not only in the regulation of GFR but also in the development of glomerulosclerosis by increasing glomerular capillary pressure caused by preferential constriction of efferent arterioles (Miller et al., 1991). The hemodynamic effects of Ang II in the kidney have been extensively reviewed elsewhere (Ichikawa and Harris, 1991; Stockand and Sansom, 1998). Besides its unique hemodynamic effects in the kidney, Ang II has been shown to have various important direct actions on mesangial cells, and these nonhemodynamic effects of Ang II may play a crucial role in Ang II-mediated glomerular injury. Mesangial cells exclusively express AT₁ receptor but not AT₂ receptor, and mesangial AT₁ receptor is coupled to G protein, causing activation of PLC (Douglas and Hopfer, 1994; Matsubara, 1998). In cultured murine mesangial cells, Ang II (10⁶ M) stimulated cellular hypertrophy, as indicated by increases in cell size and total protein content and synthesis, without an increase in [³H]thymidine incorporation, and these effects were blocked by losartan (Anderson et al., 1993). On the other hand, other investigators showed that Ang II caused not only cellular hypertrophy but also proliferation in mesangial cells (Wolf et al., 1992; Gomez-Garre et al., 1996). However, the molecular mechanism responsible for Ang II-mediated mesangial cell growth is poorly understood. Ang II activated ERK (Huwiler et al., 1995; Anderson et al., 1996) and JNK (Huwiler et al., 1998) in rat mesangial cells, although the role of ERK or JNK activation has not been defined. Ang II (10⁵ to 10⁸ M) dose dependently increased superoxide anion production in rat mesangial cells, in parallel with mesangial cell hypertrophy and proliferation, and the latter effects were completely abolished by blockade of superoxide anion production with diphenyleneiodonium chloride (10⁵ M; Jaimes et al., 1998). Furthermore, stimulation of superoxide anion production by Ang II in mesangial cells was completely blocked by PD98059 (50 µM) or calphostin C (1 µM) but not by tyrosine kinase inhibitors, herbimycin A (1 µM) and genistein (10 µM), suggesting that ERK cascade and PKC participate in mesangial cell growth by enhancing superoxide anion production.

Accumulating evidence supports the notion that TGF-1 plays a key role in progression of glomerulosclerosis by directly enhancing mesangial cell hypertrophy and ECM production (Border and Ruoslahti, 1992; Border and Noble, 1994). Glomerulosclerosis due to Ang II is postulated to be closely linked to TGF-1, as previously reviewed (Peters and Noble, 1997; Border and Noble, 1998). The treatment of rat mesangial cells with Ang II (10⁶ M) increased mRNA and protein levels for TGF-1 and ECM components including biglycan, fibronectin, and collagen type I, and neutralizing antibody to TGF-1 blocked both Ang II-induced mesangial cell hypertrophy and ECM expression, demonstrating that newly synthesized and released TGF-1 is involved in Ang II-induced mesangial cell hypertrophy and ECM production in a autocrine manner (Kagami et al., 1994). Ang II-induced fibronectin production in rat mesangial cells was mediated by PKC, as indicated by inhibition with staurosporine (10⁷ M) or H-7 (10⁶ M; Gomez-Garre et al., 1996). Ang II treatment of rat mesangial cells increased PAI-1 mRNA and protein, and anti-TGF-1 antibody inhibited Ang II-induced PAI-1 production, demonstrating the contribution of TGF-1 to Ang II-induced PAI-1 synthesis (Kagami et al., 1997). All of these in vitro findings support the notion that TGF-1 may be a key mediator in Ang II-induced glomerulosclerosis. Exposure of rat mesangial cells to Ang II increased nuclear factor-B (NF-B) DNA-binding activity, and subsequently increased MCP-1 mRNA and protein; pyrrolidine dithiocarbamate (200 µM), an antioxidant capable of inhibiting NF-B activation, abolished Ang II (10⁷ M)-induced NF-B activation and MCP-1 gene expression, suggesting that NF-B activation may be responsible for MCP-1 induction by Ang II (Ruiz-Ortega et al., 1998). Thus, Ang II also seems to be responsible for inflammatory responses of mesangial cells.

Glomerular cells are composed of not only mesangial cells but also endothelial and epithelial cells, although little is known about the role of these cells in glomerular injury. Notably, cultured rat glomerular endothelial cells were found to possess not only AT₁ receptor but also AT₂ receptor, and Ang II treatment stimulated RANTES (chemokine with chemoattractant properties for macrophages/monocytes) mRNA and protein synthesis; these processes were blocked by AT₂ receptor ligand PD123177 or CGP-42112 but not by AT₁ receptor antagonist losartan, suggesting a possible role of endothelial AT₂ receptor in Ang II-induced RANTES expression (Wolf et al., 1997). Thus, glomerular endothelial AT₂ receptor may be implicated in the development of glomerular inflammation. Glomerular epithelial cells, which play an important role as a glomerular filtration barrier, have both AT₁ and AT₂ receptors, and Ang II was shown to increase cAMP accumulation in these cells via AT₁ receptor but not AT₂ receptor (Sharma et al., 1998), although the significance of this observation is unknown.

B. Effects of In Vivo Angiotensin II Infusion on Kidney

Ang II infusion in vivo in rats was shown to cause glomerulosclerosis (Miller et al., 1991), and several important findings on cellular and molecular mechanisms of glomerular injury by Ang II infusion have been previously reported. In various types of glomerular diseases in rats and humans, glomerular mesangial cells undergo phenotypic changes, as shown by expression of significant amounts of -smooth muscle actin, which is not expressed in normal mesangial cells (Johnson et al., 1992b). Furthermore, glomerular diseases are also characterized by a significant increase in the expression of desmin, an intermediate filament, by glomerular epithelial cells. Thus, phenotypic changes in glomerular mesangial and epithelial cells are believed to play an important role in the pathophysiology of glomerular diseases. Continuous Ang II infusion (200 ng/min s.c.) in rats led to dramatic up-regulations of -smooth muscle actin in glomerular mesangial cells and desmin in epithelial cells, indicating that Ang II caused the phenotypic changes in these glomerular cells (Johnson et al., 1992a). However, the significance of these phenotypic changes induced by Ang II remains to be clarified. Continuous administration of Ang II (100 ng/min s.c.) in rats for 7 days caused increases in glomerular mRNAs for TGF-1 and collagen type I (Kagami et al., 1994). The i.p. infusion of Ang II (500 ng/h) in rats for 4 days significantly stimulated glomerular mRNA and protein expression of RANTES and increased glomerular macrophage/monocyte influx. Notably, oral treatment with PD123177 (50 mg/l drinking water) did not affect blood pressure but did attenuate glomerular RANTES expression or glomerular macrophage/monocyte influx, showing the involvement of Ang II in glomerular chemotaxis of macrophages/monocytes through local RANTES induction via AT₂ receptor (Wolf et al., 1997). Acute i.v. infusion of Ang II (100 or 1000 ng/kg/min) in conscious rats rapidly and transiently induced activation of glomerular ERK and JNK, followed by an increase in glomerular AP-1 binding activity (Hamaguchi et al., 1998). Thus, as in cardiovascular diseases, the ERK and JNK signaling cascades, via activation of AP-1, may be implicated in the development of Ang II-induced glomerular injury.

C. Effects of Angiotensin Blockade on Experimental Glomerular Diseases

Table 4 shows the potential molecular mechanisms underlying the beneficial effects of AT₁ receptor antagonists in a variety of renal disease models. In deoxycorticosterone acetate (DOCA)-salt hypertensive rats or SHRSP, which prominently exhibit progressive glomerulosclerosis, renal TGF-1 and ECM protein mRNA levels are higher than those in normotensive control rats (Kim et al., 1994b,c). Treatment of DOCA-salt hypertensive rats with candesartan cilexetil (1 mg/kg/day) or enalapril (10 mg/kg/day), although not decreasing blood pressure, significantly reduced urinary protein and albumin excretion and induced histological improvement in renal lesions, in association with decreases in renal cortical mRNA levels for TGF-1, fibronectin, laminin, and collagen types I, III, and IV (Fig. 6; Kim et al., 1994c). Also in SHRSP, candesartan cilexetil (0.1 mg/kg/day), without significantly decreasing blood pressure, significantly reduced renal TGF-1, fibronectin, laminin, and collagen types I, III, and IV mRNA levels (Kim et al., 1994b). These findings provide in vivo evidence implicating Ang II, via AT₁ receptor, in renal injury in these hypertensive models, due to enhanced renal TGF-1 and ECM expressions.

View this table: [in this window] [in a new window]   TABLE 4 Molecular effects of AT1 receptor antagonist on various glomerular disease models

View larger version (43K): [in this window] [in a new window]   Fig. 6.   Inhibitory effects of candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) on renal cortical TGF-1, collagen types I and III, and fibronectin in DOCA-salt hypertensive rats. S, sham-operated group; Ve, DOCA-salt rats treated with vehicle; Can, DOCA-salt rats treated with candesartan cilexetil; Ena, DOCA-salt rats treated with enalapril. Values are mean ± S.E. P< .05, *P< .01 versus Ve.

Nephropathy is a major cause of complications and death in DM. AT₁ receptor antagonists as well as ACE inhibitors have been shown to decrease proteinuria and slow the progression of diabetic glomerular injury in streptozotocin-induced diabetic rats (the most popular model of insulin-dependent DM; Remuzzi et al., 1993; Wolf and Ziyadeh, 1997) and OLETF rats, an NIDDM model (Kim et al., 1997c). Thus, it is possible that AT₁ receptor blockade may be effective for treating nephropathy in NIDDM patients as well as in IDDM patients, although the molecular mechanism is unknown.

In rats with subtotal renal ablation (remnant kidney model), candesartan cilexetil (1 mg/kg/day) significantly reduced the expression of glomerular -smooth muscle actin and desmin, while decreasing urinary albumin excretion and inducing histological improvement of glomerulosclerosis (Hamaguchi et al., 1996). These findings suggest a contribution of the AT₁ receptor to glomerular cell phenotypic changes in the remnant kidney model. In the rat remnant kidney model with a 40% protein diet, treatment with losartan (180 mg/l drinking water) for 8 or 14 days attenuated increases in renal TGF-1 mRNA and protein and improved glomerulosclerosis, whereas treatment with a combination of reserpine, hydralazine, and hydrochlorothiazide, despite hypotensive effects comparable with those of losartan, failed to lessen renal TGF-1 expression or glomerulosclerosis (Junaid et al., 1997). Thus, Ang II may participate in glomerulosclerosis in the remnant kidney model by enhancing glomerular TGF-1 expression.

In Thy 1.1 glomerulonephritic rats, losartan or enalapril treatment significantly, but not completely, lowered glomerular TGF-1, fibronectin, and PAI-1 mRNAs and proteins (Peters et al., 1998). In rat nephropathy induced by a daily s.c. injection of 15 mg/kg cyclosporin A (an important immunosuppressive drug), the administration of losartan (10 mg/kg) ameliorated renal lesions, with simultaneous reductions in renal cortical TGF-1, PAI-1, collagen types I and IV, and biglycan (Shihab et al., 1997). Thus, Ang II-mediated TGF-1 up-regulation may contribute to glomerulosclerosis induced by hypertension, subtotal nephrectomy, glomerulonephritis, or cyclosporin A nephropathy.

	VI. AT1 Receptor Antagonists versus Angiotensin-Converting Enzyme Inhibitors

Top Previous Next References

A. Pharmacological Differences

In humans, ACE inhibitors have been demonstrated to be powerful agents for the treatment of hypertension, congestive heart failure (The CONSENSUS Trial Study Group, 1987; The SOLVD Investigators, 1991), and renal diseases (Maschio et al., 1996) and the prevention of myocardial infarction in patients with NIDDM (Estacio et al., 1998). Recently, in elderly patients with heart failure, treatment with losartan was associated with a lower mortality rate than that found with captopril (Pitt et al., 1997). Therefore, it is a very important clinical question whether AT₁ receptor antagonists have different pharmacological actions than ACE inhibitors. Table 5 summarizes possible pharmacological differences between AT₁ receptor antagonists and ACE inhibitors. It has been well established that ACE inhibitors not only attenuate ACE-mediated formation of Ang II in the circulation and peripheral tissues but also allow the accumulation of bradykinin through the inhibition of its degradation, because ACE is identical with kininase II (Linz et al., 1995; Waeber and Brunner, 1996). The recent availability of the specific bradykinin B₂ receptor antagonist icatibant has allowed researchers to determine whether various pharmacological effects of ACE inhibitors are due to accumulated bradykinin by examining the effects of icatibant on pharmacological actions of ACE inhibitors in vitro in cultured cells or in various disease models. As reviewed in detail by Linz et al. (1995), accumulated bradykinin in tissues due to ACE inhibition contributes to blood pressure reduction in renovascular hypertensive rats, prevention of balloon injury-induced neointima formation in rat carotid artery, improvement of cardiac performance, increase in coronary blood flow, prevention of ischemia/reperfusion-induced arrhythmias, and regression of left ventricular hypertrophy in pressure-overloaded rats by aortic coarctation. Recently, it has been reported that bradykinin contributes to ACE inhibitor-induced vasodilation in the human forearm, as shown by inhibition with icatibant (Hornig et al., 1997). Furthermore, in both normotensive and hypertensive humans, bradykinin was shown to be responsible for the short-term hypotensive effect of captopril (25 mg/day), as indicated by attenuation of this effect with coadministration of icatibant (Gainer et al., 1998). Thus, accumulation of tissue bradykinin by ACE inhibitors probably produces significant beneficial effects in certain cardiovascular diseases. However, AT₁ receptor antagonists have no such action. In this regard, ACE inhibitors seem to be superior to AT₁ receptor antagonists.

View this table: [in this window] [in a new window]   TABLE 5 Comparison of in vivo pharmacological actions between AT1 receptor antagonist and ACE inhibitor

On the other hand, accumulating evidence indicates the existence of an alternative pathway for generation of Ang II, independent of ACE, in cardiovascular and renal tissues of various species, including humans (Hollenberg et al., 1998). In particular, chymase, which is a potent and specific Ang II-forming serine protease that is not affected by ACE inhibitors, has been identified in human cardiac and vascular tissues in high concentrations, suggesting that ACE inhibitors may not completely block Ang II production in human tissues (Urata et al., 1990, 1993; Shiota et al., 1993; Liao and Husain, 1995). Thus, with regard to inhibition of Ang II action via AT₁ receptor, AT₁ receptor antagonists may be superior to ACE inhibitors.

Chronic blockade of AT₁ receptor results in increased plasma renin activity and Ang II levels due to loss of the negative feedback mechanism of renin release via AT₁ receptor. Increased plasma Ang II is expected to compete with and displace AT₁ receptor antagonists at the receptor site, which may attenuate the inhibition of AT₁ receptor by these agents. Furthermore, at the same time, increased circulating Ang II is expected to activate AT₂ receptor. Interestingly, in failing human hearts, the ratio of AT₂ to AT₁ receptor is increased because of down-regulation of AT₁ receptor (Asano et al., 1997). Therefore, AT₂ receptor activation may play a key role in the pharmacological differences between AT₁ receptor antagonists and ACE inhibitors, as discussed later.

B. Is the AT₂ Receptor Beneficial or Detrimental?

There are conflicting data concerning the role of AT₂ receptor in cardiovascular and renal diseases. Furthermore, it is not easy to determine whether the effects of AT₂ receptor-selective ligands, particularly in vivo effects, represent antagonistic or agonistic actions, because the molecular, cellular, and physiological functions of AT₂ receptor have not been clearly identified. In this article, we discuss conflicting data on the functions of AT₂ receptor. The recent successful development of AT₂ receptor gene-manipulated animals has provided evidence regarding the function of AT₂ receptor in vivo (Hein, 1998). AT₂ receptor gene knockout mice exhibited a higher basal blood pressure than wild-type mice and enhanced pressor sensitivity in response to i.v. infusion of Ang II compared with the wild type, suggesting that AT₂ receptor has an opposing effect to AT₁ receptor on blood pressure in vivo (Hein et al., 1995; Ichiki et al., 1995). However, the mechanism for the hypotensive effect of AT₂ receptor remains unresolved, because AT₂ receptor expression is negligible in normal vascular tissues. Cardiac-specific overexpression of AT₂ receptor in mice produced no obvious cardiac morphological changes, but increases in blood pressure and heart rate in this transgenic model in response to Ang II infusion were significantly less than those of wild-type mice, suggesting that AT₂ receptor may decrease the sensitivity of pacemaker cells to Ang II (Masaki et al., 1998). Gene transfer of AT₂ receptor in rat carotid artery in vivo significantly decreased neointimal formation induced by balloon injury, showing the antiproliferative effect of AT₂ receptor on vascular smooth muscle cells in vivo (Nakajima et al., 1995). In rats with heart failure induced by myocardial infarction, treatment with AT₁ receptor antagonist (1.5 mg/kg/day L-158809) significantly improved cardiac hypertrophy and remodeling and cardiac dysfunction, and these effects were partially blocked by AT₂ receptor antagonist (10 mg/kg/day PD123319 via osmotic minipump), suggesting that AT₂ receptor may have the cardioprotective effects (Liu et al., 1997). Furthermore, recent in vitro studies showed that in contrast to AT₁ receptor, under certain experimental conditions, AT₂ receptor exerts antiproliferative effects on neonatal rat cardiac myocytes (Booz and Baker, 1996), fibroblasts (Ohkubo et al., 1997), and rat coronary endothelial cells (Stoll et al., 1995). All of these findings support the concept that AT₂ receptor activation may produce beneficial effects in cardiovascular diseases. An up-to-date review on the functions of this receptor, which emphasizes the beneficial role of AT₂ receptor in cardiovascular and renal diseases, was published recently (Matsubara, 1998).

However, it should be noted that conflicting data have also been reported. In global, no-flow ischemia in left atrium-perfused isolated working rat hearts, PD123,319 (0.3 µM) administered before ischemia improved the recovery of left ventricular work and efficiency, whereas losartan (1 µM) blocked the recovery of left ventricular work and depressed efficiency, suggesting that AT₂ receptor is involved in mechanical dysfunction after ischemia/reperfusion in the heart (Ford et al., 1996). The administration of PD123319 (30 mg/kg/day) in rats receiving Ang II infusion (120 ng/kg/min) had no effect on hemodynamic parameters or cardiac hypertrophy but antagonized the effects of Ang II on smooth muscle cell growth and ECM expression, whereas the administration of losartan (10 mg/kg/day) prevented Ang II-induced hemodynamic effects but did not significantly affect Ang II-induced vascular hypertrophy (Levy et al., 1996). Therefore, vascular hypertrophy and remodeling by Ang II in vivo may be mediated by AT₂ receptor rather than AT₁ receptor. Furthermore, Ang II infusion (200 ng/kg/min) in rats decreased the proliferation of left and right ventricular and right atrial myoendothelial cells, and these effects were not at all blocked by losartan treatment (10 mg/kg/day), indicating an important role of non-AT₁ receptor in the suppression of myoendothelial proliferation, although this study did not examine the effects of AT₂ receptor ligands (McEwan et al., 1998). These in vivo data support the concept that AT₂ receptor activation may have detrimental effects in cardiovascular diseases. The role of AT₂ receptor is still controversial and probably differs among various cardiovascular diseases.

C. Combination Therapy

Theoretically, monotherapy with an AT₁ receptor antagonist or ACE inhibitor may be insufficient to block the renin-angiotensin system in vivo. Indeed, in mildly salt-depleted normotensive healthy volunteers, a combination of single oral doses of captopril (50 mg) and losartan (50 mg) induced additive blood pressure reduction, whereas a combination of single oral doses of 50 mg losartan with 10 mg enalapril decreased blood pressure and stimulated plasma renin activity to a greater extent than enalapril alone at 10 to 20 mg (Azizi et al., 1997). Furthermore, recent animal studies that compared the effects of of combined AT₁ receptor antagonist and ACE inhibitor at a wide range of doses with those of each agent alone with regard to blood pressure and cardiac weight in SHR demonstrated that a low-dose combination of losartan (3 mg/kg/day) and enalapril (3 mg/kg/day) induced greater reductions in blood pressure and left ventricular weight/body weight ratio in SHR than monotherapy with higher doses (each 10 mg/kg/day) and had effects comparable with those of monotherapy with 20 mg/kg/day enalapril or 30 mg/kg/day losartan (Menard et al., 1997). In this work, as expected, the combination of enalapril with losartan in SHR prevented the increase in circulating Ang II levels observed with losartan alone, which is expected to prevent the AT₂ receptor activation that is induced by losartan alone. Furthermore, in SHR, hypotensive effects and regression of cardiac hypertrophy due to ACE inhibition are not mediated by bradykinin, as shown by the lack of effect of icatibant on the hypotensive action of ACE inhibitors in SHR (Linz et al., 1995). Therefore, these synergistic effects of combined ACE inhibitor and AT₁ receptor antagonist in SHR seem to be due not to bradykinin or AT₂ receptor but rather to more potent blockade of AT₁ receptor action. These findings clearly demonstrate that combination therapy with an AT₁ receptor antagonist and an ACE inhibitor is more effective for inhibiting the renin-angiotensin system than either agent alone and may be more powerful for cardiovascular protection than either monotherapy. However, detailed comparisons of combination therapy with monotherapy, using a broad ranges of doses and long-term treatment periods in both animal models and humans, are essential to establish the advantages and mechanisms of combination therapy using both types of drugs.

	VII. Conclusions

Top Previous Next References

There remain unresolved questions regarding the pathophysiological mechanisms of Ang II-mediated cardiovascular and renal diseases.

Although both cultured cardiac myocytes and fibroblasts in vitro significantly respond to Ang II via AT₁ receptor, the relative importance of myocytes and fibroblasts in pathological cardiac hypertrophy in vivo remains unclear. Interestingly, recent in vitro findings suggest that cardiac myocyte hypertrophy due to Ang II may be mediated by paracrine action of TGF-1, endothelin-1, or an unknown factor released from fibroblasts rather than by direct action (Sil and Sen, 1997; Gray et al., 1998). Thus, further study on cross-talk between cardiac myocytes and fibroblasts is needed to elucidate the mechanism underlying Ang II-induced pathological cardiac hypertrophy. Furthermore, it remains controversial whether cardiac Ang II actually participates in cardiac hypertrophy due to pressure overload.

Ang II, via AT₁ receptor, promotes phenotypic change and growth of cardiac, vascular, and glomerular cells and induces expression of various growth factors, ECM proteins, cytokines, and chemokines. These actions seem to play a central role in the molecular mechanism of cardiovascular hypertrophy and remodeling or glomerulosclerosis. Although AT₁ receptor is coupled to G protein and has no intrinsic tyrosine kinase activity, recent in vitro evidence suggests that AT₁ receptor activation leads to activation of not only PLC but also a variety of intracellular signal transduction cascades and transactivation of EGF or PDGF receptor. However, even in in vitro experiments, the role of these multiple signaling cascades in the above-mentioned molecular effects of Ang II remains to be elucidated, and little is known about whether AT₁ receptor activation significantly and simultaneously activates these multiple signal cascades under in vivo conditions. Future studies, particularly in vivo experiments, must determine which signal cascades activated by Ang II are responsible for cellular phenotypic change, cellular growth, and gene expression.

AT₁ receptor-mediated ERK or JNK activation may play some role in the pathophysiology of cardiovascular and renal diseases, partially mediated by activation of AP-1. Unfortunately, at present, specific and potent pharmacological inhibitors of MAP kinases or AP-1 are not available for use in in vivo experiments. Therefore, in vivo inhibition of MAP kinase activation with dominant interfering mutants of MAP kinases, using gene transfer techniques, is a powerful strategy for elucidating the role of MAP kinases in the pathophysiology of cardiovascular and renal diseases. This approach may provide important clues to in vivo molecular mechanisms of Ang II-mediated cardiovascular and renal diseases.

In vivo, Ang II exerts systemic effects, including vasoconstriction, elevation of systemic blood pressure, glomerular hypertension, activation of sympathetic nervous system, and retention of sodium and body fluids. Undoubtedly, these well known systemic effects of Ang II, with various direct molecular effects, significantly participate in the pathophysiology of cardiovascular and renal diseases in an additive or a synergistic manner. It remains unclear which is more responsible for Ang II-mediated cardiovascular and renal diseases: the molecular and cellular effects or the systemic effects. To answer this question, elucidation of the relative roles of local and circulating renin-angiotensin systems is essential. Furthermore, in vivo experiments using transgenic or knockout animals targeted to angiotensin receptor genes in a tissue-specific manner will begin to elucidate the importance of local actions of Ang II in cardiovascular and renal diseases, distinct from systemic effects. Elucidation of these questions should provide new concepts regarding the pathophysiological mechanisms of cardiovascular and renal diseases.

	Acknowledgments

Top Previous Next References

The work has been supported in part by Grants-in-Aid for Scientific Research (11670098 and 09470527) from the Ministry of Education, Science, Sports and Culture.

	Footnotes

¹ Address for correspondence: Shokei Kim, MD, PhD, Department of Pharmacology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan. E-mail: kims{at}med.osaka-cu.ac.jp

	Abbreviations

Ang II, angiotensin II; ACE, angiotensin-converting enzyme; AT₁, angiotensin II type 1; ECM, extracellular matrix; MAP, mitogen-activated protein; AT₂, angiotensin II type 2; MHC, myosin heavy chain; ANF, atrial natriuretic factor; PLC, phospholipase C; PKC, protein kinase C; ERK, extracellular signal-regulated kinase; JNK, c-jun NH2-terminal kinase; p70S6K, 70-kDa ribosomal S6 kinase; NIDDM, non-insulin-dependent diabetes mellitus; p90RSK, 90-kDa ribosomal S6 kinase; NF-B, nuclear factor-B; STAT, signal transducer and activator of transcription; TGF-1, transforming growth factor-1; MEK, mitogen-activated protein kinase kinase; AP-1, activator protein-1; SHR, spontaneously hypertensive rats; WKY, Wistar-Kyoto rats; SHRSP, stroke-prone spontaneously hypertensive rats; AC, aortocaval; DM, diabetes mellitus; OLETF, Otsuka Long-Evans Tokushima Fatty; SMC, smooth muscle cell; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; bFGF, basic fibroblast growth factor; VEGF, vascular endothelial growth factor; LDL, low-density lipoprotein; MCP-1, monocyte chemoattractant protein-1; PAI, plasminogen activator inhibitor; PI3-kinase, phosphatidylinositol 3-kinase; KDR/Flk-1, kinase domain-containing receptor/total liver kinase; DOCA, deoxycorticosterone acetate.

	References

Top Previous

• Abe J, Deguchi J, Matsumoto T, Takuwa N, Noda M, Ohno M, Makuuchi M, Kurokawa K and Takuwa Y (1997) Stimulated activation of platelet-derived growth factor receptor in vivo in balloon-injured arteries: A link between angiotensin II and intimal thickening. Circulation  96: 1906-1913[Abstract/Free Full Text].
• Abrahams C, Janicki JS and Weber KT (1987) Myocardial hypertrophy in Macaca fascicularis: Structural remodeling of the collagen matrix. Lab Invest  56: 676-683[Medline].
• Ahumada GG and Saffitz JE (1984) Fibronectin in rat heart: A link between cardiac myocytes and collagen. J Histochem Cytochem  32: 383-388[Abstract].
• Alpert NR and Mulieri LA (1982) Increased myothermal economy of isometric force generation in compensated cardiac hypertrophy induced by pulmonary artery constriction in the rabbit: A characterization of heat liberation in normal and hypertrophied right ventricular papillary muscles. Circ Res  50: 491-500[Free Full Text].
• Anderson PW, Do YS and Hsueh WA (1993) Angiotensin II causes mesangial cell hypertrophy. Hypertension  21: 29-35[Abstract/Free Full Text].
• Anderson PW, Zhang XY, Tian J, Correale JD, Xi XP, Yang D, Graf K, Law RE and Hsueh WA (1996) Insulin and angiotensin II are additive in stimulating TGF-beta 1 and matrix mRNAs in mesangial cells. Kidney Int  50: 745-753[Medline].
• Aoki H, Izumo S and Sadoshima J (1998) Angiotensin II activates RhoA in cardiac myocytes: A critical role of RhoA in angiotensin II-induced premyofibril formation. Circ Res  82: 666-676[Abstract/Free Full Text].
• Asano K, Dutcher DL, Port JD, Minobe WA, Tremmel KD, Roden RL, Bohlmeyer TJ, Bush EW, Jenkin MJ, Abraham WT, Raynolds MV, Zisman LS, Perryman MB and Bristow MR (1997) Selective downregulation of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium. Circulation  95: 1193-1200[Abstract/Free Full Text].
• Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, Tuan TL and Hsueh WA (1996) Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction. J Clin Invest  98: 2218-2227[Medline].
• Azizi M, Guyene TT, Chatellier G, Wargon M and Menard J (1997) Additive effects of losartan and enalapril on blood pressure and plasma active renin. Hypertension  29: 634-640[Abstract/Free Full Text].
• Baker KM and Aceto JF (1990) Angiotensin II stimulation of protein synthesis and cell growth in chick heart cells. Am J Physiol  259: H610-H618[Abstract/Free Full Text].
• Baker KM, Booz GW and Dostal DE (1992) Cardiac actions of angiotensin II: Role of an intracardiac renin-angiotensin system. Annu Rev Physiol  54: 227-241[Medline].
• Barany M (1967) ATPase activity of myosin correlated with speed of muscle shortening. J Gen Physiol  50 (Suppl): 197-218[Abstract/Free Full Text].
• Bauer JH and Reams GP (1995) The angiotensin II type 1 receptor antagonists: A new class of antihypertensive drugs. Arch Intern Med  155: 1361-1368[Abstract/Free Full Text].
• Berk BC and Corson MA (1997) Angiotensin II signal transduction in vascular smooth muscle: Role of tyrosine kinases. Circ Res  80: 607-616[Abstract/Free Full Text].
• Berk BC, Vekshtein V, Gordon HM and Tsuda T (1989) Angiotensin II-stimulated protein synthesis in cultured vascular smooth muscle cells. Hypertension  13: 305-314[Abstract/Free Full Text].
• Bernstein KE, Ali MS, Sayeski PP, Semeniuk D and Marrero MB (1998) New insights into the cellular signaling of seven transmembrane receptors: The role of tyrosine phosphorylation. Lab Invest  78: 3-7[Medline].
• Bhat GJ, Thekkumkara TJ, Thomas WG, Conrad KM and Baker KM (1994) Angiotensin II stimulates sis-inducing factor-like DNA binding activity: Evidence that the AT1A receptor activates transcription factor-Stat91 and/or a related protein. J Biol Chem  269: 31443-31449[Abstract/Free Full Text].
• Bishopric NH, Jayasena V and Webster KA (1992) Positive regulation of the skeletal -actin gene by fos and jun in cardiac myocytes. J Biol Chem  267: 25535-25540[Abstract/Free Full Text].
• Booz GW and Baker KM (1996) Role of type 1 and type 2 angiotensin receptors in angiotensin II-induced cardiomyocyte hypertrophy. Hypertension  28: 635-640[Abstract/Free Full Text].
• Border WA and Noble NA (1994) Transforming growth factor beta in tissue fibrosis. N Engl J Med  331: 1286-1292[Free Full Text].
• Border WA and Noble NA (1998) Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. Hypertension  31: 181-188[Abstract/Free Full Text].
• Border WA and Ruoslahti E (1992) Transforming growth factor- in disease: The dark side of tissue repair. J Clin Invest  90: 1-7.
• Brilla CG, Maisch B and Weber KT (1992) Myocardial collagen matrix remodelling in arterial hypertension. Eur Heart J  13: 24-32.
• Brown L and Sernia C (1994) Angiotensin receptors in cardiovascular diseases. Clin Exp Pharmacol Physiol  21: 811-818[Medline].
• Campbell SE and Katwa LC (1997) Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. J Mol Cell Cardiol  29: 1947-1958[Medline].
• Capers Q, Laursen JB, Fukui K, Rajagopalan S, Mori I, Lou P, Freeman BA, Berrington WR, Griendling KK, Harrison DG, Runge MS, Alexander RW and Taylor WR (1997) Vascular thrombin receptor regulation in hypertensive rats. Circ Res  80: 838-844[Abstract/Free Full Text].
• Chen XL, Tummala PE, Olbrych MT, Alexander RW and Medford RM (1998) Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. Circ Res  83: 952-959[Abstract/Free Full Text].
• Chiu AT, Herblin WF, McCall DE, Ardecky RJ, Carini DJ, Duncia JV, Pease LJ, Wong PC, Wexler RR, Johnson AL and Timmermans PBMWM (1989) Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun  165: 196-203[Medline].
• Chobanian AV, Haudenschild CC, Nickerson C and Drago R (1990) Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension  15: 327-331[Abstract/Free Full Text].
• Crabos M, Roth M, Hahn AW and Erne P (1994) Characterization of angiotensin II receptors in cultured adult rat cardiac fibroblasts: Coupling to signaling systems and gene expression. J Clin Invest  93: 2372-2378.
• Daemen MJ, Lombardi DM, Bosman FT and Schwartz SM (1991) Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res  68: 450-456[Abstract/Free Full Text].
• Delafontaine P and Lou H (1993) Angiotensin II regulates insulin-like growth factor I gene expression in vascular smooth muscle cells. J Biol Chem  268: 16866-16870[Abstract/Free Full Text].
• Doering CW, Jalil JE, Janicki JS, Pick R, Aghili S, Abrahams C and Weber KT (1988) Collagen network remodelling and diastolic stiffness of the rat left ventricle with pressure overload hypertrophy. Cardiovasc Res  22: 686-695[Medline].
• Dostal DE and Baker KM (1992) Angiotensin II stimulation of left ventricular hypertrophy in adult rat heart: Mediation by the AT1 receptor. Am J Hypertens  5: 276-280[Medline].
• Dostal DE, Booz GW and Baker KM (1996) Angiotensin II signalling pathways in cardiac fibroblasts: Conventional versus novel mechanisms in mediating cardiac growth and function. Mol Cell Biochem  157: 15-21[Medline].
• Douglas JG and Hopfer U (1994) Novel aspect of angiotensin receptors and signal transduction in the kidney. Annu Rev Physiol  56: 649-669[Medline].
• Duff JL, Berk BC and Corson MA (1992) Angiotensin II stimulates the pp44 and pp42 mitogen-activated protein kinases in cultured rat aortic smooth muscle cells. Biochem Biophys Res Commun  188: 257-264[Medline].
• Eguchi S, Numaguchi K, Iwasaki H, Matsumoto T, Yamakawa T, Utsunomiya H, Motley ED, Kawakatsu H, Owada KM, Hirata Y, Marumo F and Inagami T (1998) Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. J Biol Chem  273: 8890-8896[Abstract/Free Full Text].
• Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N and Schrier RW (1998) The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med  338: 645-652[Abstract/Free Full Text].
• Everett AD, Tufro-McReddie A, Fisher A and Gomez RA (1994) Angiotensin receptor regulates cardiac hypertrophy and transforming growth factor-beta 1 expression. Hypertension  23: 587-592[Abstract/Free Full Text].
• Feener EP, Northrup JM, Aiello LP and King GL (1995) Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells. J Clin Invest  95: 1353-1362.
• Feuvray D, Idell-Wenger JA and Neely JR (1979) Effects of ischemia on rat myocardial function and metabolism in diabetes. Circ Res  44: 322-329[Free Full Text].
• Force T, Pombo CM, Avruch JA, Bonventre JV and Kyriakis JM (1996) Stress-activated protein kinases in cardiovascular disease. Circ Res.  78: 947-953[Free Full Text].
• Ford WR, Clanachan AS and Jugdutt BI (1996) Opposite effects of angiotensin AT1 and AT2 receptor antagonists on recovery of mechanical function after ischemia-reperfusion in isolated working rat hearts. Circulation  94: 3087-3089[Abstract/Free Full Text].
• Gainer JV, Morrow JD, Loveland A, King DJ and Brown NJ (1998) Effect of bradykinin-receptor blockade on the response to angiotensin-converting enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med  339: 1285-1292[Abstract/Free Full Text].
• Geisterfer AA, Peach MJ and Owens GK (1988) Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res  62: 749-756[Abstract/Free Full Text].
• Giasson E and Meloche S (1995) Role of p70 S6 protein kinase in angiotensin II-induced protein synthesis in vascular smooth muscle cells. J Biol Chem  270: 5225-5231[Abstract/Free Full Text].
• Gibbons GH and Dzau VJ (1994) The emerging concept of vascular remodeling. N Engl J Med  330: 1431-1438[Free Full Text].
• Gibbons GH, Pratt RE and Dzau VJ (1992) Vascular smooth muscle cell hypertrophy vs. hyperplasia: Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II. J Clin Invest  90: 456-461.
• Glennon PE, Kaddoura S, Sale EM, Sale GJ, Fuller SJ and Sugden PH (1996) Depletion of mitogen-activated protein kinase using an antisense oligodeoxynucleotide approach downregulates the phenylephrine-induced hypertrophic response in rat cardiac myocytes. Circ Res  78: 954-961[Abstract/Free Full Text].
• Gomez-Garre D, Ruiz-Ortega M, Ortego M, Largo R, Lopez-Armada MJ, Plaza JJ, Gonzalez E and Egido J (1996) Effects and interactions of endothelin-1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. Hypertension  27: 885-892[Abstract/Free Full Text].
• Grafe M, Auch-Schwelk W, Zakrzewicz A, Regitz-Zagrosek V, Bartsch P, Graf K, Loebe M, Gaehtgens P and Fleck E (1997) Angiotensin II-induced leukocyte adhesion on human coronary endothelial cells is mediated by E-selectin. Circ Res  81: 804-811[Abstract/Free Full Text].
• Gray MO, Long CS, Kalinyak JE, Li HT and Karliner JS (1998) Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from fibroblasts. Cardiovasc Res  40: 352-363[Abstract/Free Full Text].
• Griendling KK, Minieri CA, Ollerenshaw JD and Alexander RW (1994) Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res  74: 1141-1148[Abstract/Free Full Text].
• Griendling KK, Ushio-Fukai M, Lassegue B and Alexander RW (1997) Angiotensin II signaling in vascular smooth muscle: New concepts. Hypertension  29: 366-373[Abstract/Free Full Text].
• Griffin SA, Brown WC, MacPherson F, McGrath JC, Wilson VG, Korsgaard N, Mulvany MJ and Lever AF (1991) Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism. Hypertension  17: 626-635[Abstract/Free Full Text].
• Hamaguchi A, Kim S, Izumi Y, Zhan Y, Yamanaka S and Iwao H (1999) Contribution of extracellular signal-regulated kinase to angiotensin II-induced transforming growth factor-1 expression in vascular smooth muscle cells. Hypertension  34: 126-131[Abstract/Free Full Text].
• Hamaguchi A, Kim S, Wanibuchi H and Iwao H (1996) Angiotensin II and calcium blockers prevent glomerular phenotypic changes in remnant kidney models. J Am Soc Nephrol  7: 687-693[Abstract].
• Hamaguchi A, Kim S, Yano M, Yamanaka S and Iwao H (1998) Activation of glomerular mitogen-activated protein kinases in angiotensin II-mediated hypertension. J Am Soc Nephrol  9: 372-380[Abstract].
• Hanatani A, Yoshiyama M, Kim S, Omura T, Toda I, Akioka K, Teragaki M, Takeuchi K, Iwao H and Takeda T (1995) Inhibition by angiotensin II type 1 receptor antagonist of cardiac phenotypic modulation after myocardial infarction. J Mol Cell Cardiol  27: 1905-1914[Medline].
• Hanson SR, Powell JS, Dodson T, Lumsden A, Kelly AB, Anderson JS, Clowes AW and Harker LA (1991) Effects of angiotensin converting enzyme inhibition with cilazapril on intimal hyperplasia in injured arteries and vascular grafts in the baboon. Hypertension  18 (suppl II): II-70-II-76.
• Harada K, Komuro I, Shiojima I, Hayashi D, Kudoh S, Mizuno T, Kijima K, Matsubara H, Sugaya T, Murakami K and Yazaki Y (1998a) Pressure overload induces cardiac hypertrophy in angiotensin II type 1A receptor knockout mice. Circulation  97: 1952-1959[Abstract/Free Full Text].
• Harada K, Komuro I, Zou Y, Kudoh S, Kijima K, Matsubara H, Sugaya T, Murakami K and Yazaki Y (1998b) Acute pressure overload could induce hypertrophic responses in the heart of angiotensin II type 1a knockout mice. Circ Res  82: 779-785[Abstract/Free Full Text].
• Hayashida W, Horiuchi M and Dzau VJ (1996) Intracellular third loop domain of angiotensin II type-2 receptor: Role in mediating signal transduction and cellular function. J Biol Chem  271: 21985-21992[Abstract/Free Full Text].
• Hein L (1998) Genetic deletion and overexpression of angiotensin II receptors. J Mol Med  76: 756-763[Medline].
• Hein L, Barsh GS, Pratt RE, Dzau VJ and Kobilka BK (1995) Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. Nature (Lond)  377: 744-747[Medline].
• Henegar JR, Schwartz DD and Janicki JS (1998) Ang II-related myocardial damage: role of cardiac sympathetic catecholamines and beta-receptor regulation. Am J Physiol  275: H534-H541.
• Hewett TE, Grupp IL, Grupp G and Robbins J (1994) Alpha-skeletal actin is associated with increased contractility in the mouse heart. Circ Res  74: 740-746[Abstract/Free Full Text].
• Hollenberg NK, Fisher ND and Price DA (1998) Pathways for angiotensin II generation in intact human tissue: Evidence from comparative pharmacological interruption of the renin system. Hypertension  32: 387-392[Abstract/Free Full Text].
• Horackova M and Armour JA (1997) ANG II modifies cardiomyocyte function via extracardiac and intracardiac neurons: In situ and in vitro studies. Am J Physiol  272: R766-R775[Abstract/Free Full Text].
• Hornig B, Kohler C and Drexler H (1997) Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation  95: 1115-1118[Abstract/Free Full Text].
• Huckle WR, Drag MD, Acker WR, Powers M, McFall RC, Holder DJ, Fujita T, Stabilito II, Kim D, Ondeyka DL, Mantlo NB, Chang RS, Reilly CF, Schwartz RS, Greenlee WJ and Johnson RG, Jr (1996) Effects of subtype-selective and balanced angiotensin II receptor antagonists in a porcine coronary artery model of vascular restenosis. Circulation  93: 1009-1019[Abstract/Free Full Text].
• Huwiler A, Stabel S, Fabbro D and Pfeilschifter J (1995) Platelet-derived growth factor and angiotensin II stimulate the mitogen-activated protein kinase cascade in renal mesangial cells: Comparison of hypertrophic and hyperplastic agonists. Biochem J  305: 777-784.
• Huwiler A, van Rossum G, Wartmann M and Pfeilschifter J (1998) Angiotensin II stimulation of the stress-activated protein kinases in renal mesangial cells is mediated by the angiotensin AT1 receptor subtype. Eur J Pharmacol  343: 297-302[Medline].
• Ichikawa I and Harris RC (1991) Angiotensin actions in the kidney: Renewed insight into the old hormone. Kidney Int  40: 583-596[Medline].
• Ichiki T, Labosky PA, Shiota C, Okuyama S, Imagawa Y, Fogo A, Niimura F, Ichikawa I, Hogan BL and Inagami T (1995) Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature (Lond)  377: 748-750[Medline].
• Imai T, Hirata Y, Emori T, Yanagisawa M, Masaki T and Marumo F (1992) Induction of endothelin-1 gene by angiotensin and vasopressin in endothelial cells. Hypertension  19: 753-757[Abstract/Free Full Text].
• Ingelfinger JR and Dzau VJ (1991) Molecular biology of renal injury: emphasis on the role of the renin-angiotensin system. J Am Soc Nephrol  2 (suppl 1): S9-S20[Abstract].
• Ishida M, Marrero MB, Schieffer B, Ishida T, Bernstein KE and Berk BC (1995) Angiotensin II activates pp60c-src in vascular smooth muscle cells. Circ Res  77: 1053-1059[Abstract/Free Full Text].
• Ishizaka N, de Leon H, Laursen JB, Fukui T, Wilcox JN, De Keulenaer G, Griendling KK and Alexander RW (1997) Angiotensin II-induced hypertension increases heme oxygenase-1 expression in rat aorta. Circulation  96: 1923-1929[Abstract/Free Full Text].
• Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Murumo F and Hiroe M (1993) Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest  92: 398-403.
• Iwami K, Ashizawa N, Do YS, Graf K and Hsueh WA (1996) Comparison of Ang II with other growth factors on Egr-1 and matrix gene expression in cardiac fibroblasts. Am J Physiol  270: H2100-H2107[Abstract/Free Full Text].
• Izumi Y, Kim S, Murakami T, Yamanaka S and Iwao H (1998) Cardiac mitogen-activated protein kinase activities are chronically increased in stroke-prone hypertensive rats. Hypertension  31: 50-56[Abstract/Free Full Text].
• Izumo S, Lompre AM, Matsuoka R, Koren G, Schwartz K, Nadal-Ginard B and Mahdavi V (1987) Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy: Interaction between hemodynamic and thyroid hormone-induced signals. J Clin Invest  79: 970-977.
• Izumo S, Nadal-Ginard B and Mahdavi V (1988) Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci USA  85: 339-343[Abstract/Free Full Text].
• Jaimes EA, Galceran JM and Raij L (1998) Angiotensin II induces superoxide anion production by mesangial cells. Kidney Int  54: 775-784[Medline].
• Jalil JE, Doering CW, Janicki JS, Pick R, Shroff SG and Weber KT (1989) Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res  64: 1041-1050[Abstract/Free Full Text].
• Johnson RJ, Alpers CE, Yoshimura A, Lombardi D, Pritzl P, Floege J and Schwartz SM (1992a) Renal injury from angiotensin II-mediated hypertension. Hypertension  19: 464-474[Abstract/Free Full Text].
• Johnson RJ, Floege J, Yoshimura A, Iida H, Couser WG and Alpers CE (1992b) The activated mesangial cell: A glomerular "myofibroblast"? J Am Soc Nephrol  2: S190-S197[Abstract].
• Johnston CI (1995) Angiotensin receptor antagonists: Focus on losartan. Lancet  346: 1403-1407[Medline].
• Junaid A, Rosenberg ME and Hostetter TH (1997) Interaction of angiotensin II and TGF-beta 1 in the rat remnant kidney. J Am Soc Nephrol  8: 1732-1738[Abstract].
• Kagami S, Border WA, Miller DE and Noble NA (1994) Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor- expression in rat glomerular mesangial cells. J Clin Invest  93: 2431-2437.
• Kagami S, Kuhara T, Okada K, Kuroda Y, Border WA and Noble NA (1997) Dual effects of angiotensin II on the plasminogen/plasmin system in rat mesangial cells. Kidney Int  51: 664-671[Medline].
• Karin M (1995) The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem  270: 16483-16486[Free Full Text].
• Katai H, Stephenson JD, Simkevich CP, Thompson JP and Raghow R (1992) An AP-1-like motif in the first intron of human Pro alpha 1(I) collagen gene is a critical determinant of its transcriptional activity. Mol Cell Biochem  118: 119-129[Medline].
• Kato H, Suzuki H, Tajima S, Ogata Y, Tominaga T, Sato A and Saruta T (1991) Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens  9: 17-22[Medline].
• Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M and Natori T (1992) Spontaneous long-term hyperglycemic rat with diabetic complications: Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes  41: 1422-1428[Abstract].
• Keidar S and Attias J (1997) Angiotensin II injection into mice increases the uptake of oxidized LDL by their macrophages via a proteoglycan-mediated pathway. Biochem Biophys Res Commun  239: 63-67[Medline].
• Keidar S, Attias J, Smith J, Breslow JL and Hayek T (1997) The angiotensin-II receptor antagonist, losartan, inhibits LDL lipid peroxidation and atherosclerosis in apolipoprotein E-deficient mice. Biochem Biophys Res Commun  236: 622-625[Medline].
• Kent RL and McDermott PJ (1996) Passive load and angiotensin II evoke differential responses of gene expression and protein synthesis in cardiac myocytes. Circ Res  78: 829-838[Abstract/Free Full Text].
• Kim S, Hamaguchi A, Shinkawa T, Kato Y, Tsuchiya N, Miura K, Ohta K and Iwao H (1996a) Molecular effects of M17055, furosemide and thiazide on cardiac hypertrophy of spontaneously hypertensive rats. J Pharmacol Exp Ther  279: 983-990[Abstract/Free Full Text].
• Kim S, Izumi Y, Yano M, Hamaguchi A, Miura K, Yamanaka S, Miyazaki H and Iwao H (1998) Angiotensin blockade inhibits activation of mitogen-activated protein kinases in rat balloon-injured artery. Circulation  97: 1731-1737[Abstract/Free Full Text].
• Kim S, Kawamura M, Wanibuchi H, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K and Iwao H (1995a) Angiotensin II type 1 receptor blockade inhibits the expression of immediate-early genes and fibronectin in rat injured artery. Circulation  92: 88-95[Abstract/Free Full Text].
• Kim S, Murakami T, Izumi Y, Yano M, Miura K, Yamanaka S and Iwao H (1997a) Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activities are continuously and differentially increased in aorta of hypertensive rats. Biochem Biophys Res Commun  236: 199-204[Medline].
• Kim S, Ohta K, Hamaguchi A, Omura T, Tominaga K, Yukimura T, Miura K, Tanaka M and Iwao H (1994a) AT1 receptor-mediated stimulation by angiotensin II of rat aortic fibronectin gene expression in vivo. Br J Pharmacol  113: 662-663[Medline].
• Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y, Ishimura Y, Chatani F and Iwao H (1995b) Angiotensin II type I receptor antagonist inhibits the gene expression of transforming growth factor-beta 1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther  273: 509-515[Abstract/Free Full Text].
• Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y, Wada T, Ishimura Y, Chatani F and Iwao H (1994b) Contribution of renal angiotensin II type I receptor to gene expressions in hypertension-induced renal injury. Kidney Int  46: 1346-1358[Medline].
• Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y, Wada T, Ishimura Y, Chatani F and Iwao H (1994c) Role of angiotensin II in renal injury of deoxycorticosterone acetate-salt hypertensive rats. Hypertension  24: 195-204[Abstract/Free Full Text].
• Kim S, Ohta K, Hamaguchi A, Yukimura T, Miura K and Iwao H (1995c) Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats. Hypertension  25: 1252-1259[Abstract/Free Full Text].
• Kim S, Ohta K, Hamaguchi A, Yukimura T, Miura K and Iwao H (1996b) Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats. Br J Pharmacol  118: 549-556[Medline].
• Kim S, Sada T, Mizuno M, Ikeda M, Yano M, Miura K, Yamanaka S, Koike H and Iwao H (1997b) Effects of angiotensin AT1 receptor antagonist on volume overload-induced cardiac gene expression in rats. Hypertens Res  20: 133-142[Medline].
• Kim S, Wanibuchi H, Hamaguchi A, Miura K, Yamanaka S and Iwao H (1997c) Angiotensin blockade improves cardiac and renal complications of type II diabetic rats. Hypertension  30: 1054-1061[Abstract/Free Full Text].
• Kim SJ, Angel P, Lafyatis R, Hattori K, Kim KY, Sporn MB, Karin M and Roberts AB (1990) Autoinduction of transforming growth factor-1 is mediated by the AP-1 complex. Mol Cell Biol  10: 1492-1497[Abstract/Free Full Text].
• Kim SJ, Glick A, Sporn MB and Roberts AB (1989) Characterization of the promoter region of the human transforming growth factor-1 gene. J Biol Chem  264: 402-408[Abstract/Free Full Text].
• Kodama H, Fukuda K, Pan J, Makino S, Sano M, Takahashi T, Hori S and Ogawa S (1998) Biphasic activation of the JAK/STAT pathway by angiotensin II in rat cardiomyocytes. Circ Res  82: 244-250[Abstract/Free Full Text].
• Kudoh S, Komuro I, Mizuno T, Yamazaki T, Zou Y, Shiojima I, Takekoshi N and Yazaki Y (1997) Angiotensin II stimulates c-Jun NH2-terminal kinase in cultured cardiac myocytes of neonatal rats. Circ Res  80: 139-146[Abstract/Free Full Text].
• Kusuhara M, Takahashi E, Peterson TE, Abe J, Ishida M, Han J, Ulevitch R and Berk BC (1998) p38 Kinase is a negative regulator of angiotensin II signal transduction in vascular smooth muscle cells: Effects on Na⁺/H⁺ exchange and ERK1/2. Circ Res  83: 824-831[Abstract/Free Full Text].
• Laursen JB, Rajagopalan S, Galis Z, Tarpey M, Freeman BA and Harrison DG (1997) Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation  95: 588-593[Abstract/Free Full Text].
• Leduc I, Haddad P, Giasson E and Meloche S (1995) Involvement of a tyrosine kinase pathway in the growth-promoting effects of angiotensin II on aortic smooth muscle cells. Mol Pharmacol  48: 582-592[Abstract].
• Leduc I and Meloche S (1995) Angiotensin II stimulates tyrosine phosphorylation of the focal adhesion-associated protein paxillin in aortic smooth muscle cells. J Biol Chem  270: 4401-4404[Abstract/Free Full Text].
• Lee MA, Bohm M, Kim S, Bachmann S, Bachmann J, Bader M and Ganten D (1995) Differential gene expression of renin and angiotensinogen in the TGR(mREN-2)27 transgenic rat. Hypertension  25: 570-580[Abstract/Free Full Text].
• Levy BI, Benessiano J, Henrion D, Caputo L, Heymes C, Duriez M, Poitevin P and Samuel JL (1996) Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure. J Clin Invest  98: 418-425[Medline].
• Liao Y and Husain A (1995) The chymase-angiotensin system in humans: biochemistry, molecular biology and potential role in cardiovascular diseases. Can J Cardiol  11: 13F-19F.
• Linseman DA, Benjamin CW and Jones DA (1995) Convergence of angiotensin II and platelet-derived growth factor receptor signaling cascades in vascular smooth muscle cells. J Biol Chem  270: 12563-12568[Abstract/Free Full Text].
• Linz W, Wiemer G, Gohlke P, Unger T and Scholkens BA (1995) Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev  47: 25-49[Abstract].
• Litwin SE, Raya TE, Anderson PG, Daugherty S and Goldman S (1990) Abnormal cardiac function in the streptozotocin-diabetic rat: Changes in active and passive properties of the left ventricle. J Clin Invest  86: 481-488.
• Liu Y, Leri A, Li B, Wang X, Cheng W, Kajstura J and Anversa P (1998) Angiotensin II stimulation in vitro induces hypertrophy of normal and postinfarcted ventricular myocytes. Circ Res  82: 1145-1159[Abstract/Free Full Text].
• Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E and Carretero OA (1997) Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure: Role of kinins and angiotensin II type 2 receptors. J Clin Invest  99: 1926-1935[Medline].
• Lompre AM, Nadal-Ginard B and Mahdavi V (1984) Expression of the cardiac ventricular alpha- and beta-myosin heavy chain genes is developmentally and hormonally regulated. J Biol Chem  259: 6437-6446[Abstract/Free Full Text].
• Low BC, Ross IK and Grigor MR (1992) Angiotensin II stimulates glucose transport activity in cultured vascular smooth muscle cells. J Biol Chem  267: 20740-20745[Abstract/Free Full Text].
• Mahgoub MA and Abd-Elfattah AS (1998) Diabetes mellitus and cardiac function. Mol Cell Biochem  180: 59-64[Medline].
• Majesky MW, Reidy MA, Bowen-Pope DF, Hart CE, Wilcox JN and Schwartz SM (1990) PDGF ligand and receptor gene expression during repair of arterial injury. J Cell Biol  111: 2149-2158[Abstract/Free Full Text].
• Marrero MB, Paxton WG, Duff JL, Berk BC and Bernstein KE (1994) Angiotensin II stimulates tyrosine phosphorylation of phospholipase C-gamma 1 in vascular smooth muscle cells. J Biol Chem  269: 10935-10939[Abstract/Free Full Text].
• Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P and Bernstein KE (1995) Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature (Lond)  375: 247-250[Medline].
• Masaki H, Kurihara T, Yamaki A, Inomata N, Nozawa Y, Mori Y, Murasawa S, Kizima K, Maruyama K, Horiuchi M, Dzau VJ, Takahashi H, Iwasaka T, Inada M and Matsubara H (1998) Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects. J Clin Invest  101: 527-535[Medline].
• Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E and Zucchelli P (1996) Effect of the angiotensin-converting enzyme inhibitor benazepril on the progression of chronic renal insufficiency: The Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med  334: 939-945[Abstract/Free Full Text].
• Matsubara H (1998) Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ Res  83: 1182-1191[Abstract/Free Full Text].
• Mayer Y, Czosnek H, Zeelon PE, Yaffe D and Nudel U (1984) Expression of the genes coding for the skeletal muscle and cardiac actions in the heart. Nucleic Acids Res  12: 1087-1100[Abstract/Free Full Text].
• McEwan PE, Gray GA, Sherry L, Webb DJ and Kenyon CJ (1998) Differential effects of angiotensin II on cardiac cell proliferation and intramyocardial perivascular fibrosis in vivo. Circulation  98: 2765-2773[Abstract/Free Full Text].
• Menard J, Campbell DJ, Azizi M and Gonzales MF (1997) Synergistic effects of ACE inhibition and Ang II antagonism on blood pressure, cardiac weight, and renin in spontaneously hypertensive rats. Circulation  96: 3072-3078[Abstract/Free Full Text].
• Miano JM, Tota RR, Vlasic N, Danishefsky KJ and Stemerman MB (1990) Early proto-oncogene expression in rat aortic smooth muscle cells following endothelial removal. Am J Pathol  137: 761-765[Abstract].
• Miller PL, Rennke HG and Meyer TW (1991) Glomerular hypertrophy accelerates hypertensive glomerular injury in rats. Am J Physiol  261: F459-F465[Abstract/Free Full Text].
• Minty AJ, Alonso S, Caravatti M and Buckingham ME (1982) Afetal skeletal muscle actin mRNA in the mouse and its identity with cardiac actin mRNA . Cell  30: 185-192[Medline].
• Molloy CJ, Taylor DS and Weber H (1993) Angiotensin II stimulation of rapid protein tyrosine phosphorylation and protein kinase activation in rat aortic smooth muscle cells. J Biol Chem  268: 7338-7345[Abstract/Free Full Text].
• Mullins JJ, Peters J and Ganten D (1990) Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature (Lond)  344: 541-544[Medline].
• Murphy TJ, Alexander RW, Griendling KK, Runge MS and Bernstein KE (1991) Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature (Lond)  351: 233-236[Medline].
• Naftilan AJ, Pratt RE and Dzau VJ (1989) Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest  83: 1419-1424.
• Nakajima M, Hutchinson HG, Fujinaga M, Hayashida W, Morishita R, Zhang L, Horiuchi M, Pratt RE and Dzau VJ (1995) The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: Gain-of-function study using gene transfer. Proc Natl Acad Sci USA  92: 10663-10667[Abstract/Free Full Text].
• Nakamura K, Fushimi K, Kouchi H, Mihara K, Miyazaki M, Ohe T and Namba M (1998) Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor- and angiotensin II. Circulation  98: 794-799[Abstract/Free Full Text].
• Ohkubo N, Matsubara H, Nozawa Y, Mori Y, Murasawa S, Kijima K, Maruyama K, Masaki H, Tsutumi Y, Shibazaki Y, Iwasaka T and Inada M (1997) Angiotensin type 2 receptors are reexpressed by cardiac fibroblasts from failing myopathic hamster hearts and inhibit cell growth and fibrillar collagen metabolism. Circulation  96: 3954-3962[Abstract/Free Full Text].
• Ohta K, Kim S, Hamaguchi A, Yukimura T, Miura K, Takaori K and Iwao H (1994) Role of angiotensin II in extracellular matrix and transforming growth factor-beta 1 expression in hypertensive rats. Eur J Pharmacol  269: 115-119[Medline].
• Ohta K, Kim S and Iwao H (1996a) Role of angiotensin-converting enzyme, adrenergic receptors, and blood pressure in cardiac gene expression of spontaneously hypertensive rats during development. Hypertension  28: 627-634[Abstract/Free Full Text].
• Ohta K, Kim S, Wanibuchi H, Ganten D and Iwao H (1996b) Contribution of local renin-angiotensin system to cardiac hypertrophy, phenotypic modulation, and remodeling in TGR(mRen2)27 transgenic rats. Circulation  94: 785-791[Abstract/Free Full Text].
• Otani A, Takagi H, Suzuma K and Honda Y (1998) Angiotensin II potentiates vascular endothelial growth factor-induced angiogenic activity in retinal microcapillary endothelial cells. Circ Res  82: 619-628[Abstract/Free Full Text].
• Pan J, Fukuda K, Kodama H, Makino S, Takahashi T, Sano M, Hori S and Ogawa S (1997) Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart. Circ Res  81: 611-617[Abstract/Free Full Text].
• Parker TG (1995) Molecular biology of myocardial hypertrophy and failure: gene expression and trophic signaling. New Horiz  3: 288-300[Medline].
• Parker TG and Schneider MD (1991) Growth factors, proto-oncogenes, and plasticity of the cardiac phenotype. Annu Rev Physiol  53: 179-200[Medline].
• Pelouch V, Dixon IM, Golfman L, Beamish RE and Dhalla NS (1993) Role of extracellular matrix proteins in heart function. Mol Cell Biochem  129: 101-120[Medline].
• Peters H, Border WA and Noble NA (1998) Targeting TGF-beta overexpression in renal disease: Maximizing the antifibrotic action of angiotensin II blockade. Kidney Int  54: 1570-1580[Medline].
• Peters H and Noble NA (1997) Angiotensin II and L-arginine in tissue fibrosis: More than blood pressure. Kidney Int  51: 1481-1486[Medline].
• Pitt B and Konstam MA (1998) Overview of angiotensin II-receptor antagonists. Am J Cardiol  82: 47S-49S[Medline].
• Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, Deedwania PC, Ney DE, Snavely DB and Chang PI (1997) Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet  349: 747-752[Medline].
• Polte TR, Naftilan AJ and Hanks SK (1994) Focal adhesion kinase is abundant in developing blood vessels and elevation of its phosphotyrosine content in vascular smooth muscle cells is a rapid response to angiotensin II. J Cell Biochem  55: 106-119[Medline].
• Powell JS, Clozel JP, Muller RK, Kuhn H, Hefti F, Hosang M and Baumgartner HR (1989) Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science (Wash DC)  245: 186-188[Abstract/Free Full Text].
• Prescott MF, Webb RL and Reidy MA (1991) Angiotensin-converting enzyme inhibitor versus angiotensin II, AT1 receptor antagonist. Am J Pathol  139: 1291-1296[Abstract].
• Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK and Harrison DG (1996) Angiotensin II mediated hypertension in the rat increases vascular superoxide production via membrane NAPD/NADPH oxidase activation: Contribution to alteration of vasomotor tone. J Clin Invest  97: 1916-1923[Medline].
• Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmad MR and Haider B (1977) Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest  60: 885-899.
• Remuzzi A, Perico N, Amuchastegui CS, Malanchini B, Mazerska M, Battaglia C, Bertani T and Remuzzi G (1993) Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes. J Am Soc Nephrol  4: 40-49[Abstract].
• Ritchie RH, Schiebinger RJ, LaPointe MC and Marsh JD (1998) Angiotensin II-induced hypertrophy of adult rat cardiomyocytes is blocked by nitric oxide. Am J Physiol  275: H1370-H1374[Abstract/Free Full Text].
• Ruiz-Ortega M, Bustos C, Hernandez-Presa MA, Lorenzo O, Plaza JJ and Egido J (1998) Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor-kappa B activation and monocyte chemoattractant protein-1 synthesis. J Immunol  161: 430-439[Abstract/Free Full Text].
• Rump LC, Schwertfeger E, Schaible U, Fraedrich G and Schollmeyer P (1994) Beta 2-adrenergic receptor and angiotensin II receptor modulation of sympathetic neurotransmission in human atria. Circ Res  74: 434-440[Abstract/Free Full Text].
• Ruzicka M, Keeley FW and Leenen FH (1994a) The renin-angiotensin system and volume overload-induced changes in cardiac collagen and elastin. Circulation  90: 1989-1996[Abstract/Free Full Text].
• Ruzicka M, Yuan B and Leenen FH (1994b) Effects of enalapril versus losartan on regression of volume overload-induced cardiac hypertrophy in rats. Circulation  90: 484-491[Abstract/Free Full Text].
• Sadoshima J and Izumo S (1993) Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts: Critical role of the AT1 receptor subtype. Circ Res  73: 413-423[Abstract/Free Full Text].
• Sadoshima J and Izumo S (1995) Rapamycin selectively inhibits angiotensin II-induced increase in protein synthesis in cardiac myocytes in vitro: Potential role of 70-kDS6 kinase in angiotensin II-induced cardiac hypertrophy. Circ Res  77: 1040-1052[Abstract/Free Full Text].
• Sadoshima J and Izumo S (1997) The cellular and molecular response of cardiac myocytes to mechanical stress. Annu Rev Physiol  59: 551-571[Medline].
• Sadoshima J, Qiu Z, Morgan JP and Izumo S (1995) Angiotensin II and other hypertrophic stimuli mediated by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90-kDS6 kinase in cardiac myocytes: The critical role of Ca²⁺-dependent signaling. Circ Res  76: 1-15[Abstract/Free Full Text].
• Sadoshima J, Xu Y, Slayter HS and Izumo S (1993) Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell  75: 977-984[Medline].
• Sasaki K, Yamano Y, Bardhan S, Iwai N, Murray JJ, Hasegawa M, Matsuda Y and Inagami T (1991) Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type-1 receptor. Nature (Lond)  351: 230-233[Medline].
• Saward L and Zahradka P (1997) Angiotensin II activates phosphatidylinositol 3-kinase in vascular smooth muscle cells. Circ Res  81: 249-257[Abstract/Free Full Text].
• Sayeski PP, Ali MS, Harp JB, Marrero MB and Bernstein KE (1998) Phosphorylation of p130Cas by angiotensin II is dependent on c-Src, intracellular Ca²⁺, and protein kinase C. Circ Res  82: 1279-1288[Abstract/Free Full Text].
• Schieffer B, Bernstein KE and Marrero MB (1996) The role of tyrosine phosphorylation in angiotensin II mediated intracellular signaling and cell growth. J Mol Med  74: 85-91[Medline].
• Schieffer B, Wirger A, Meybrunn M, Seitz S, Holtz J, Riede UN and Drexler H (1994) Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat. Circulation  89: 2273-2282[Abstract/Free Full Text].
• Schmitz U, Ishida T, Ishida M, Surapisitchat J, Hasham MI, Pelech S and Berk BC (1998) Angiotensin II stimulates p21-activated kinase in vascular smooth muscle cells: Role in activation of JNK. Circ Res  82: 1272-1278[Abstract/Free Full Text].
• Schorb W, Booz GW, Dostal DE, Conrad KM, Chang KC and Baker KM (1993) Angiotensin II is mitogenic in neonatal rat cardiac fibroblasts. Circ Res  72: 1245-1254[Abstract/Free Full Text].
• Schorb W, Peeler TC, Madigan NN, Conrad KM and Baker KM (1994) Angiotensin II-induced protein tyrosine phosphorylation in neonatal rat cardiac fibroblasts. J Biol Chem  269: 19626-19632[Abstract/Free Full Text].
• Schuh JR, Blehm DJ, Frierdich GE, McMahon EG and Blaine EH (1993) Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits. J Clin Invest  91: 1453-1458.
• Schunkert H, Sadoshima J, Cornelius T, Kagaya Y, Weinberg EO, Izumo S, Riegger G and Lorell BH (1995) Angiotensin II-induced growth responses in isolated adult rat hearts: Evidence for load-independent induction of cardiac protein synthesis by angiotensin II. Circ Res  76: 489-497[Abstract/Free Full Text].
• Schwartz K, Chassagne C and Boheler KR (1993) The molecular biology of heart failure. J Am Coll Cardiol  22: 30A-33A.
• Schwartz K, de la Bastie D, Bouveret P, Oliviero P, Alonso S and Buckingham M (1986) Alpha-skeletal muscle actin mRNAs accumulate in hypertrophied adult rat hearts. Circ Res  59: 551-555[Abstract/Free Full Text].
• Sechi LA, Griffin CA and Schambelan M (1994) The cardiac renin-angiotensin system in STZ-induced diabetes. Diabetes  43: 1180-1184[Abstract].
• Seikaly MG, Arant BS, Jr and Seney FD, Jr (1990) Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. J Clin Invest  86: 1352-1357.
• Servant MJ, Giasson E and Meloche S (1996) Inhibition of growth factor-induced protein synthesis by a selective MEK inhibitor in aortic smooth muscle cells. J Biol Chem  271: 16047-16052[Abstract/Free Full Text].
• Sharifi BG, LaFleur DW, Pirola CJ, Forrester JS and Fagin JA (1992) Angiotensin II regulates tenascin gene expression in vascular smooth muscle cells. J Biol Chem  267: 23910-23915[Abstract/Free Full Text].
• Sharma M, Sharma R, Greene AS, McCarthy ET and Savin VJ (1998) Documentation of angiotensin II receptors in glomerular epithelial cells. Am J Physiol  274: F623-F627.
• Shihab FS, Bennett WM, Tanner AM and Andoh TF (1997) Angiotensin II blockade decreases TGF-beta1 and matrix proteins in cyclosporine nephropathy. Kidney Int  52: 660-673[Medline].
• Shiota N, Okunishi H, Fukamizu A, Sakonjo H, Kikumori M, Nishimura T, Nakagawa T, Murakami K and Miyazaki M (1993) Activation of two angiotensin-generating systems in the balloon-injured artery. FEBS Lett  323: 239-242[Medline].
• Sil P and Sen S (1997) Angiotensin II and myocyte growth: Role of fibroblasts. Hypertension  30: 209-216[Abstract/Free Full Text].
• Silver PJ, Cumiskey WR and Harris AL (1992) Vascular protein kinase C in Wistar-Kyoto and spontaneously hypertensive rats. Eur J Pharmacol  212: 143-149[Medline].
• Simon G and Altman S (1992) Subpressor angiotensin II is a bifunctional growth factor of vascular muscle in rats. J Hypertens  10: 1165-1171[Medline].
• Stockand JD and Sansom SC (1998) Glomerular mesangial cells: electrophysiology and regulation of contraction. Physiol Rev  78: 723-744[Abstract/Free Full Text].
• Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R and Unger T (1995) The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest  95: 651-657.
• Su EJ, Lombardi DM, Wiener J, Daemen MJ, Reidy MA and Schwartz SM (1998) Mitogenic effect of angiotensin II on rat carotid arteries and type II or III mesenteric microvessels but not type I mesenteric microvessels is mediated by endogenous basic fibroblast growth factor. Circ Res  82: 321-327[Abstract/Free Full Text].
• Sugano M, Makino N and Yanaga T (1996) The effects of renin-angiotensin system inhibition on aortic cholesterol content in cholesterol-fed rabbits. Atherosclerosis  127: 123-129[Medline].
• Sugaya T, Nishimatsu S, Tanimoto K, Takimoto E, Yamagishi T, Imamura K, Goto S, Imaizumi K, Hisada Y, Otsuka A, Fukamizu A and Murakami K (1995) Angiotensin II type 1a receptor-deficient mice with hypotension and hyperreninemia. J Biol Chem  270: 18719-18722[Abstract/Free Full Text].
• Sugden PH and Clerk A (1998a) Cellular mechanisms of cardiac hypertrophy. J Mol Med  76: 725-746[Medline].
• Sugden PH and Clerk A (1998b) "Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res  83: 345-352[Free Full Text].
• Takahashi E, Abe J and Berk BC (1997) Angiotensin II stimulates p90rsk in vascular smooth muscle cells: A potential Na⁺-H⁺ exchanger kinase. Circ Res  81: 268-273[Abstract/Free Full Text].
• Takano H, Komuro I, Zou Y, Kudoh S, Yamazaki T and Yazaki Y (1996) Activation of p70 S6 protein kinase is necessary for angiotensin II-induced hypertrophy in neonatal rat cardiac myocytes. FEBS Lett  379: 255-259[Medline].
• Tamura K, Nyui N, Tamura N, Fujita T, Kihara M, Toya Y, Takasaki I, Takagi N, Ishii M, Oda K, Horiuchi M and Umemura S (1998) Mechanism of angiotensin II-mediated regulation of fibronectin gene in rat vascular smooth muscle cells. J Biol Chem  273: 26487-26496[Abstract/Free Full Text].
• Tan LB, Jalil JE, Pick R, Janicki JS and Weber KT (1991) Cardiac myocyte necrosis induced by angiotensin II. Circ Res  69: 1185-1195[Abstract/Free Full Text].
• The CONSENSUS Trial Study Group (1987) Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med  316: 1429-1435[Abstract].
• The MERCATOR Study Group (1992) Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: A multicenter, randomized, double-blind placebo-controlled trial. Circulation  86: 100-110[Abstract/Free Full Text].
• The SOLVD Investigators (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med  325: 293-302[Abstract].
• Thienelt CD, Weinberg EO, Bartunek J and Lorell BH (1997) Load-induced growth responses in isolated adult rat hearts: Role of the AT1 receptor. Circulation  95: 2677-2683[Abstract/Free Full Text].
• Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler R, Saye J and Smith R (1993) Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev  45: 205-251[Medline].
• Tsuda T, Kawahara Y, Ishida Y, Koide M, Shii K and Yokoyama M (1992) Angiotensin II stimulates two myelin basic protein/microtubule-associated protein 2 kinases in cultured vascular smooth muscle cells. Circ Res  71: 620-630[Abstract/Free Full Text].
• Unger T, Chung O, Csikos T, Culman J, Gallinat S, Gohlke P, Hohle S, Meffert S, Stoll M, Stroth U and Zhu YZ (1996) Angiotensin receptors. J Hypertens  14 (suppl): S95-S103.
• Urata H, Boehm KD, Philip A, Kinoshita A, Gabrovsek J, Bumpus FM and Husain A (1993) Cellular localization and regional distribution of an angiotensin II-forming chymase in the heart. J Clin Invest  91: 1269-1281.
• Urata H, Kinoshita A, Misono KS, Bumpus FM and Husain A (1990) Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem  265: 22348-22357[Abstract/Free Full Text].
• Villarreal FJ and Dillmann WH (1992) Cardiac hypertrophy-induced changes in mRNA levels for TGF-beta 1, fibronectin, and collagen. Am J Physiol  262: H1861-H1866[Abstract/Free Full Text].
• Villarreal FJ, Kim NN, Ungab GD, Printz MP and Dillmann WH (1993) Identification of functional angiotensin II receptors on rat cardiac fibroblasts. Circulation  88: 2849-2861[Abstract/Free Full Text].
• Wada H, Zile MR, Ivester CT, Cooper GT and McDermott PJ (1996) Comparative effects of contraction and angiotensin II on growth of adult feline cardiocytes in primary culture. Am J Physiol  271: H29-H37[Abstract/Free Full Text].
• Waeber B and Brunner HR (1996) Cardiovascular hypertrophy: Role of angiotensin II and bradykinin. J Cardiovasc Pharmacol  27: S36-S40.
• Wang Y, Su B, Sah VP, Brown JH, Han J and Chien KR (1998) Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells. J Biol Chem  273: 5423-5426[Abstract/Free Full Text].
• Weber H, Taylor DS and Molloy CJ (1994a) Angiotensin II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells: Correlation with the expression of specific endogenous growth factors and reversal by suramin. J Clin Invest  93: 788-798.
• Weber KT (1997) Extracellular matrix remodeling in heart failure: A role for de novo angiotensin II generation. Circulation  96: 4065-4082[Free Full Text].
• Weber KT, Sun Y, Tyagi SC and Cleutjens JP (1994b) Collagen network of the myocardium: Function, structural remodeling and regulatory mechanisms. J Mol Cell Cardiol  26: 279-292[Medline].
• Wesson LG (1998) Physical factors and glomerulosclerosis: Cause or coincidence? Nephron  78: 125-130[Medline].
• Williams B, Baker AQ, Gallacher B and Lodwick D (1995) Angiotensin II increases vascular permeability factor gene expression by human vascular smooth muscle cells. Hypertension  25: 913-917[Abstract/Free Full Text].
• Wolf G, Haberstroh U and Neilson EG (1992) Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells. Am J Pathol  140: 95-107[Abstract].
• Wolf G and Ziyadeh FN (1997) The role of angiotensin II in diabetic nephropathy: emphasis on nonhemodynamic mechanisms. Am J Kidney Dis  29: 153-163[Medline].
• Wolf G, Ziyadeh FN, Thaiss F, Tomaszewski J, Caron RJ, Wenzel U, Zahner G, Helmchen U and Stahl RA (1997) Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells: Role of the angiotensin type 2 receptor. J Clin Invest  100: 1047-1058[Medline].
• Yagi K, Kim S, Wanibuchi H, Yamashita T, Yamamura Y and Iwao H (1997) Characteristics of diabetes, blood pressure, and cardiac and renal complications in Otsuka Long-Evans Tokushima Fatty rats. Hypertension  29: 728-735[Abstract/Free Full Text].
• Yamada T, Horiuchi M and Dzau VJ (1996) Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci U S A  93: 156-160[Abstract/Free Full Text].
• Yang BC, Phillips MI, Mohuczy D, Meng H, Shen L, Mehta P and Mehta JL (1998) Increased angiotensin II type 1 receptor expression in hypercholesterolemic atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol  18: 1433-1439[Abstract/Free Full Text].
• Yano M, Kim S, Izumi Y, Yamanaka S and Iwao H (1998) Differential activation of cardiac c-jun amino-terminal kinase and extracellular signal-regulated kinase in angiotensin II-mediated hypertension. Circ Res  83: 752-760[Abstract/Free Full Text].
• Yoshiyama M, Takeuchi K, Omura T, Kim S, Yamagishi H, Toda I, Teragaki M, Akioka K, Iwao H and Yoshikawa J (1999) Effects of candesartan and cilazapril on rats with myocardial infarction assessed by echocardiography. Hypertension  33: 961-968[Abstract/Free Full Text].
• Zhang J and Pratt RE (1996) The AT2 receptor selectively associates with Gi-alpha2 and Gi-alpha3 in the rat fetus. J Biol Chem  271: 15026-15033[Abstract/Free Full Text].
• Zimmerman BG (1981) Adrenergic facilitation by angiotensin: Does it serve a physiological function? Clin Sci  60: 343-348[Medline].
• Zou Y, Komuro I, Yamazaki T, Kudoh S, Aikawa R, Zhu W, Shiojima I, Hiroi Y, Tobe K, Kadowaki T and Yazaki Y (1998) Cell type-specific angiotensin II-evoked signal transduction pathways: Critical roles of G-beta-gamma subunit, Src family, and Ras in cardiac fibroblasts. Circ Res  82: 337-345[Abstract/Free Full Text].

0031-6997/00/5201-0011$03.00/0
PHARMACOLOGICAL REVIEWS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				P. Castro-Chaves, R. Fontes-Carvalho, M. Pintalhao, P. Pimentel-Nunes, and A. F. Leite-Moreira Angiotensin II-induced increase in myocardial distensibility and its modulation by the endocardial endothelium in the rabbit heart Exp Physiol, June 1, 2009; 94(6): 665 - 674. [Abstract] [Full Text] [PDF]

				H.-H. Hsu, K. Duning, H. H. Meyer, M. Stolting, T. Weide, S. Kreusser, T. van Le, C. Gerard, R. Telgmann, S.-M. Brand-Herrmann, et al. Hypertension in mice lacking the CXCR3 chemokine receptor Am J Physiol Renal Physiol, April 1, 2009; 296(4): F780 - F789. [Abstract] [Full Text] [PDF]

				E. M. de Cavanagh, M. Ferder, F. Inserra, and L. Ferder Angiotensin II, mitochondria, cytoskeletal, and extracellular matrix connections: an integrating viewpoint Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H550 - H558. [Abstract] [Full Text] [PDF]

				G.-X. Zhang, S. Kimura, K. Murao, J. Shimizu, H. Matsuyoshi, and M. Takaki Role of neuronal NO synthase in regulating vascular superoxide levels and mitogen-activated protein kinase phosphorylation Cardiovasc Res, February 1, 2009; 81(2): 389 - 399. [Abstract] [Full Text] [PDF]

				S. Zhu, Y. Liu, L. Wang, and Q. H. Meng Transforming growth factor-{beta}1 is associated with kidney damage in patients with essential hypertension: renoprotective effect of ACE inhibitor and/or angiotensin II receptor blocker Nephrol. Dial. Transplant., September 1, 2008; 23(9): 2841 - 2846. [Abstract] [Full Text] [PDF]

				E. Yamamoto, Y.-F. Dong, K. Kataoka, T. Yamashita, Y. Tokutomi, S. Matsuba, H. Ichijo, H. Ogawa, and S. Kim-Mitsuyama Olmesartan Prevents Cardiovascular Injury and Hepatic Steatosis in Obesity and Diabetes, Accompanied by Apoptosis Signal Regulating Kinase-1 Inhibition Hypertension, September 1, 2008; 52(3): 573 - 580. [Abstract] [Full Text] [PDF]

				K. Block, A. Eid, K. K. Griendling, D.-Y. Lee, Y. Wittrant, and Y. Gorin Nox4 NAD(P)H Oxidase Mediates Src-dependent Tyrosine Phosphorylation of PDK-1 in Response to Angiotensin II: ROLE IN MESANGIAL CELL HYPERTROPHY AND FIBRONECTIN EXPRESSION J. Biol. Chem., August 29, 2008; 283(35): 24061 - 24076. [Abstract] [Full Text] [PDF]

				B. Chandrasekaran, O. Dar, and T. McDonagh The role of apelin in cardiovascular function and heart failure Eur J Heart Fail, August 1, 2008; 10(8): 725 - 732. [Abstract] [Full Text] [PDF]

				C. Ootaki, M. Yamashita, Y. Ootaki, K. Kamohara, S. Weber, R. S. Klatte, W. A. Smith, A. L. Massiello, S. N. Emancipator, L. A.R. Golding, et al. Reduced Pulsatility Induces Periarteritis in Kidney: Role of the Local Renin-Angiotensin System J. Thorac. Cardiovasc. Surg., July 1, 2008; 136(1): 150 - 158. [Abstract] [Full Text] [PDF]

				S. Sriramula, M. Haque, D. S.A. Majid, and J. Francis Involvement of Tumor Necrosis Factor-{alpha} in Angiotensin II-Mediated Effects on Salt Appetite, Hypertension, and Cardiac Hypertrophy Hypertension, May 1, 2008; 51(5): 1345 - 1351. [Abstract] [Full Text] [PDF]

				F. Cosentino, P. Francia, G. G. Camici, P. G. Pelicci, M. Volpe, and T. F. Luscher Final Common Molecular Pathways of Aging and Cardiovascular Disease: Role of the p66Shc Protein Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 622 - 628. [Abstract] [Full Text] [PDF]

				S.-Y. Kim, R. Gul, S.-Y. Rah, S. H. Kim, S. K. Park, M.-J. Im, H. J. Kwon, and U.-H. Kim Molecular mechanism of ADP-ribosyl cyclase activation in angiotensin II signaling in murine mesangial cells Am J Physiol Renal Physiol, April 1, 2008; 294(4): F982 - F989. [Abstract] [Full Text] [PDF]

				T. Nakamura, E. Yamamoto, K. Kataoka, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Beneficial Effects of Pioglitazone on Hypertensive Cardiovascular Injury Are Enhanced by Combination With Candesartan Hypertension, February 1, 2008; 51(2): 296 - 301. [Abstract] [Full Text] [PDF]

				A. Yogi, C. Mercure, J. Touyz, G. E. Callera, A. C.I. Montezano, A. B. Aranha, R. C. Tostes, T. Reudelhuber, and R. M. Touyz Renal Redox-Sensitive Signaling, but Not Blood Pressure, Is Attenuated by Nox1 Knockout in Angiotensin II-Dependent Chronic Hypertension Hypertension, February 1, 2008; 51(2): 500 - 506. [Abstract] [Full Text] [PDF]

				O. W. van den Brink, L. M D. Delbridge, T. Pedrazzini, F. L Rosenfeldt, and S. Pepe Augmented myocardial methionine-enkephalin in a murine model of cardiac angiotensin II-overexpression Journal of Renin-Angiotensin-Aldosterone System, December 1, 2007; 8(4): 153 - 159. [Abstract] [PDF]

				E. Mendez-Bolaina, J. Sanchez-Gonzalez, I. Ramirez-Sanchez, E. Ocharan-Hernandez, M. Nunez-Sanchez, E. Meaney-Mendiolea, A. Meaney, J. Asbun-Bojalil, A. Miliar-Garcia, I. Olivares-Corichi, et al. Effect of caveolin-1 scaffolding peptide and 17 -estradiol on intracellular Ca2+ kinetics evoked by angiotensin II in human vascular smooth muscle cells Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1953 - C1961. [Abstract] [Full Text] [PDF]

				T. J. Guzik, N. E. Hoch, K. A. Brown, L. A. McCann, A. Rahman, S. Dikalov, J. Goronzy, C. Weyand, and D. G. Harrison Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction J. Exp. Med., October 1, 2007; 204(10): 2449 - 2460. [Abstract] [Full Text] [PDF]

				E. Yamamoto, K. Kataoka, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Role of Xanthine Oxidoreductase in the Reversal of Diastolic Heart Failure by Candesartan in the Salt-Sensitive Hypertensive Rat Hypertension, October 1, 2007; 50(4): 657 - 662. [Abstract] [Full Text] [PDF]

				H. Kobori, M. Nangaku, L. G. Navar, and A. Nishiyama The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease Pharmacol. Rev., September 1, 2007; 59(3): 251 - 287. [Abstract] [Full Text] [PDF]

				S. Choudhary, M. Lu, R. Cui, and A. R. Brasier Involvement of a Novel Rac/RhoA Guanosine Triphosphatase-Nuclear Factor-{kappa}B Inducing Kinase Signaling Pathway Mediating Angiotensin II-Induced RelA Transactivation Mol. Endocrinol., September 1, 2007; 21(9): 2203 - 2217. [Abstract] [Full Text] [PDF]

				A. Kilic, A. Bubikat, B. Gassner, H. A. Baba, and M. Kuhn Local Actions of Atrial Natriuretic Peptide Counteract Angiotensin II Stimulated Cardiac Remodeling Endocrinology, September 1, 2007; 148(9): 4162 - 4169. [Abstract] [Full Text] [PDF]

				P. deS. Senanayake, J. Drazba, K. Shadrach, A. Milsted, E. Rungger-Brandle, K. Nishiyama, S.-I. Miura, S. Karnik, J. E. Sears, and J. G. Hollyfield Angiotensin II and Its Receptor Subtypes in the Human Retina Invest. Ophthalmol. Vis. Sci., July 1, 2007; 48(7): 3301 - 3311. [Abstract] [Full Text] [PDF]

				J. C. Q. Velez, A. M. Bland, J. M. Arthur, J. R. Raymond, and M. G. Janech Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes Am J Physiol Renal Physiol, July 1, 2007; 293(1): F398 - F407. [Abstract] [Full Text] [PDF]

				W. M Maharsy, L. N Kadi, N. G Issa, K. M Bitar, A. H Der-Boghossian, R. Abrahamian, and A. B Bikhazi Cross-talk related to insulin and angiotensin II binding on myocardial remodelling in diabetic rat hearts Journal of Renin-Angiotensin-Aldosterone System, June 1, 2007; 8(2): 59 - 65. [Abstract] [PDF]

				H.-L. Li, Z.-G. She, T.-B. Li, A.-B. Wang, Q. Yang, Y.-S. Wei, Y.-G. Wang, and D.-P. Liu Overexpression of Myofibrillogenesis Regulator-1 Aggravates Cardiac Hypertrophy Induced by Angiotensin II in Mice Hypertension, June 1, 2007; 49(6): 1399 - 1408. [Abstract] [Full Text] [PDF]

				M. Sanchez, F. Lodi, R. Vera, I. C. Villar, A. Cogolludo, R. Jimenez, L. Moreno, M. Romero, J. Tamargo, F. Perez-Vizcaino, et al. Quercetin and Isorhamnetin Prevent Endothelial Dysfunction, Superoxide Production, and Overexpression of p47phox Induced by Angiotensin II in Rat Aorta J. Nutr., April 1, 2007; 137(4): 910 - 915. [Abstract] [Full Text] [PDF]

				E. Yamamoto, T. Yamashita, T. Tanaka, K. Kataoka, Y. Tokutomi, Z.-F. Lai, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Pravastatin Enhances Beneficial Effects of Olmesartan on Vascular Injury of Salt-Sensitive Hypertensive Rats, via Pleiotropic Effects Arterioscler. Thromb. Vasc. Biol., March 1, 2007; 27(3): 556 - 563. [Abstract] [Full Text] [PDF]

				M. Cotton, P.-L. Boulay, T. Houndolo, N. Vitale, J. A. Pitcher, and A. Claing Endogenous ARF6 Interacts with Rac1 upon Angiotensin II Stimulation to Regulate Membrane Ruffling and Cell Migration Mol. Biol. Cell, February 1, 2007; 18(2): 501 - 511. [Abstract] [Full Text] [PDF]

				Y. Soga, S. Takai, H. Okabayashi, A. Nagasawa, T. Yokota, K. Nishimura, M. Miyazaki, and M. Komeda Human gastroepiploic artery has greater chymase activity than the internal thoracic artery Eur. J. Cardiothorac. Surg., December 1, 2006; 30(6): 877 - 880. [Abstract] [Full Text] [PDF]

				M. P. Ocaranza, I. Godoy, J. E. Jalil, M. Varas, P. Collantes, M. Pinto, M. Roman, C. Ramirez, M. Copaja, G. Diaz-Araya, et al. Enalapril Attenuates Downregulation of Angiotensin-Converting Enzyme 2 in the Late Phase of Ventricular Dysfunction in Myocardial Infarcted Rat Hypertension, October 1, 2006; 48(4): 572 - 578. [Abstract] [Full Text] [PDF]

				F. H. Messerli and J. A. Staessen Amlodipine Better Than Lisinopril?: How One Randomized Clinical Trial Ended Fallacies From Observational Studies Hypertension, September 1, 2006; 48(3): 359 - 361. [Full Text] [PDF]

				M. M. Martin, E. J. Lee, J. A. Buckenberger, T. D. Schmittgen, and T. S. Elton MicroRNA-155 Regulates Human Angiotensin II Type 1 Receptor Expression in Fibroblasts J. Biol. Chem., July 7, 2006; 281(27): 18277 - 18284. [Abstract] [Full Text] [PDF]

				M. Buraczynska, P. Ksiazek, A. Drop, W. Zaluska, D. Spasiewicz, and A. Ksiazek Genetic polymorphisms of the renin-angiotensin system in end-stage renal disease Nephrol. Dial. Transplant., April 1, 2006; 21(4): 979 - 983. [Abstract] [Full Text] [PDF]

				N. S. Dhalla, M. R. Dent, P. S. Tappia, R. Sethi, J. Barta, and R. K. Goyal Subcellular Remodeling as a Viable Target for the Treatment of Congestive Heart Failure Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2006; 11(1): 31 - 45. [Abstract] [PDF]

				Z. Ying, L. Jin, T. Palmer, and R. C. Webb Angiotensin II Up-Regulates the Leukemia-Associated Rho Guanine Nucleotide Exchange Factor (RhoGEF), a Regulator of G Protein Signaling Domain-Containing RhoGEF, in Vascular Smooth Muscle Cells Mol. Pharmacol., March 1, 2006; 69(3): 932 - 940. [Abstract] [Full Text] [PDF]

				M. C. Liebau, D. Lang, J. Bohm, N. Endlich, M. J. Bek, I. Witherden, P. W. Mathieson, M. A. Saleem, H. Pavenstadt, and K.-G. Fischer Functional expression of the renin-angiotensin system in human podocytes Am J Physiol Renal Physiol, March 1, 2006; 290(3): F710 - F719. [Abstract] [Full Text] [PDF]

				J. Bolbrinker, S. Markovic, M. Wehland, W. B. W. H. Melenhorst, H. van Goor, and R. Kreutz Expression and Response to Angiotensin-Converting Enzyme Inhibition of Matrix Metalloproteinases 2 and 9 in Renal Glomerular Damage in Young Transgenic Rats with Renin-Dependent Hypertension J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 8 - 16. [Abstract] [Full Text] [PDF]

				E. C. Miner and W. L. Miller A Look Between the Cardiomyocytes: The Extracellular Matrix in Heart Failure Mayo Clin. Proc., January 1, 2006; 81(1): 71 - 76. [Abstract] [Full Text] [PDF]

				J. Wang, P. Paradis, A. Aries, H. Komati, C. Lefebvre, H. Wang, and M. Nemer Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4 Mol. Cell. Biol., November 15, 2005; 25(22): 9829 - 9844. [Abstract] [Full Text] [PDF]

				E. A. Woolfolk, S. Eguchi, H. Ohtsu, H. Nakashima, H. Ueno, W. T. Gerthoffer, and E. D. Motley Angiotensin II-induced activation of p21-activated kinase 1 requires Ca2+ and protein kinase C{delta} in vascular smooth muscle cells Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1286 - C1294. [Abstract] [Full Text] [PDF]

				K. Matsuno, H. Yamada, K. Iwata, D. Jin, M. Katsuyama, M. Matsuki, S. Takai, K. Yamanishi, M. Miyazaki, H. Matsubara, et al. Nox1 Is Involved in Angiotensin II-Mediated Hypertension: A Study in Nox1-Deficient Mice Circulation, October 25, 2005; 112(17): 2677 - 2685. [Abstract] [Full Text] [PDF]

				T. Ibaraki, M. Muramatsu, S. Takai, D. Jin, H. Maruyama, T. Orino, T. Katsumata, and M. Miyazaki The relationship of tryptase- and chymase-positive mast cells to angiogenesis in stage I non-small cell lung cancer Eur. J. Cardiothorac. Surg., October 1, 2005; 28(4): 617 - 621. [Abstract] [Full Text] [PDF]

				A. Page, H. Reich, J. Zhou, V. Lai, D. C. Cattran, J. W. Scholey, and J. A. Miller Endothelial Nitric Oxide Synthase Gene/Gender Interactions and the Renal Hemodynamic Response to Angiotensin II J. Am. Soc. Nephrol., October 1, 2005; 16(10): 3053 - 3060. [Abstract] [Full Text] [PDF]

				Y. Nagai, K. Miyata, G.-P. Sun, M. Rahman, S. Kimura, A. Miyatake, H. Kiyomoto, M. Kohno, Y. Abe, M. Yoshizumi, et al. Aldosterone Stimulates Collagen Gene Expression and Synthesis Via Activation of ERK1/2 in Rat Renal Fibroblasts Hypertension, October 1, 2005; 46(4): 1039 - 1045. [Abstract] [Full Text] [PDF]

				H. Ohtsu, M. Mifune, G. D. Frank, S. Saito, T. Inagami, S. Kim-Mitsuyama, Y. Takuwa, T. Sasaki, J. D. Rothstein, H. Suzuki, et al. Signal-Crosstalk Between Rho/ROCK and c-Jun NH2-Terminal Kinase Mediates Migration of Vascular Smooth Muscle Cells Stimulated by Angiotensin II Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1831 - 1836. [Abstract] [Full Text] [PDF]

				F. Bouzeghrane, D. P. Reinhardt, T. L. Reudelhuber, and G. Thibault Enhanced expression of fibrillin-1, a constituent of the myocardial extracellular matrix in fibrosis Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H982 - H991. [Abstract] [Full Text] [PDF]

				G. Graiani, C. Lagrasta, E. Migliaccio, F. Spillmann, M. Meloni, P. Madeddu, F. Quaini, I. M. Padura, L. Lanfrancone, P. Pelicci, et al. Genetic Deletion of the p66Shc Adaptor Protein Protects From Angiotensin II-Induced Myocardial Damage Hypertension, August 1, 2005; 46(2): 433 - 440. [Abstract] [Full Text] [PDF]

				M. Mifune, H. Ohtsu, H. Suzuki, H. Nakashima, E. Brailoiu, N. J. Dun, G. D. Frank, T. Inagami, S. Higashiyama, W. G. Thomas, et al. G Protein Coupling and Second Messenger Generation Are Indispensable for Metalloprotease-dependent, Heparin-binding Epidermal Growth Factor Shedding through Angiotensin II Type-1 Receptor J. Biol. Chem., July 15, 2005; 280(28): 26592 - 26599. [Abstract] [Full Text] [PDF]

				P. Hernandez-Vargas, O. Lopez-Franco, G. Sanjuan, M. Ruperez, G. Ortiz-Munoz, Y. Suzuki, P. Aguado-Roncero, G. Perez-Tejerizo, J. Blanco, J. Egido, et al. Suppressors of Cytokine Signaling Regulate Angiotensin II-Activated Janus Kinase-Signal Transducers and Activators of Transcription Pathway in Renal Cells J. Am. Soc. Nephrol., June 1, 2005; 16(6): 1673 - 1683. [Abstract] [Full Text] [PDF]

				S. Wesseling, D. A. Ishola Jr., J. A. Joles, H. A. Bluyssen, H. A. Koomans, and B. Braam Resistance to oxidative stress by chronic infusion of angiotensin II in mouse kidney is not mediated by the AT2 receptor Am J Physiol Renal Physiol, June 1, 2005; 288(6): F1191 - F1200. [Abstract] [Full Text] [PDF]

				S R. Sprovieri and Y A. Sens Polymorphisms of the renin-angiotensin system genes in Brazilian patients with lupus nephropathy Lupus, May 1, 2005; 14(5): 356 - 362. [Abstract] [PDF]

				S. Kim-Mitsuyama, E. Yamamoto, T. Tanaka, Y. Zhan, Y. Izumi, Y. Izumiya, T. Ioroi, H. Wanibuchi, and H. Iwao Critical Role of Angiotensin II in Excess Salt-Induced Brain Oxidative Stress of Stroke-Prone Spontaneously Hypertensive Rats Stroke, May 1, 2005; 36(5): 1077 - 1082. [Abstract] [Full Text] [PDF]

				C. Vecchione, E. Patrucco, G. Marino, L. Barberis, R. Poulet, A. Aretini, A. Maffei, M. T. Gentile, M. Storto, O. Azzolino, et al. Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3K{gamma} J. Exp. Med., April 18, 2005; 201(8): 1217 - 1228. [Abstract] [Full Text] [PDF]

				W. G. Barnes, E. Reiter, J. D. Violin, X.-R. Ren, G. Milligan, and R. J. Lefkowitz {beta}-Arrestin 1 and G{alpha}q/11 Coordinately Activate RhoA and Stress Fiber Formation following Receptor Stimulation J. Biol. Chem., March 4, 2005; 280(9): 8041 - 8050. [Abstract] [Full Text] [PDF]

				A. Morganti Should a Diuretic Always Be the First Choice in Patients with Essential Hypertension? The Case for No J. Am. Soc. Nephrol., March 1, 2005; 16(3_suppl_1): S70 - S73. [Abstract] [Full Text] [PDF]

				M. Fujita, I. Hayashi, S. Yamashina, A. Fukamizu, M. Itoman, and M. Majima Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth Carcinogenesis, February 1, 2005; 26(2): 271 - 279. [Abstract] [Full Text] [PDF]

				A. C. Hakam and T. Hussain Renal Angiotensin II Type-2 Receptors Are Upregulated and Mediate the Candesartan-Induced Natriuresis/Diuresis in Obese Zucker Rats Hypertension, February 1, 2005; 45(2): 270 - 275. [Abstract] [Full Text] [PDF]

				T. Watanabe, T. A. Barker, and B. C. Berk Angiotensin II and the Endothelium: Diverse Signals and Effects Hypertension, February 1, 2005; 45(2): 163 - 169. [Abstract] [Full Text] [PDF]

				W. Xiang, J. Kong, S. Chen, L.-P. Cao, G. Qiao, W. Zheng, W. Liu, X. Li, D. G. Gardner, and Y. C. Li Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E125 - E132. [Abstract] [Full Text] [PDF]

				J. P. Casas, A. D. Hingorani, L. E. Bautista, and P. Sharma Meta-analysis of Genetic Studies in Ischemic Stroke: Thirty-two Genes Involving Approximately 18 000 Cases and 58 000 Controls Arch Neurol, November 1, 2004; 61(11): 1652 - 1661. [Abstract] [Full Text] [PDF]

				F. Schwartz, A. Duka, I. Duka, J. Cui, and H. Gavras Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H1957 - H1966. [Abstract] [Full Text] [PDF]

				G. F. Tomaselli and D. P. Zipes What Causes Sudden Death in Heart Failure? Circ. Res., October 15, 2004; 95(8): 754 - 763. [Abstract] [Full Text] [PDF]

				B. E. Thomas and T. J. Thekkumkara Glucose Mediates Transcriptional Repression of the Human Angiotensin Type-1 Receptor Gene: Role for a Novel Cis-acting Element Mol. Biol. Cell, October 1, 2004; 15(10): 4347 - 4355. [Abstract] [Full Text] [PDF]

				A. Lundequist, E. Tchougounova, M. Abrink, and G. Pejler Cooperation between Mast Cell Carboxypeptidase A and the Chymase Mouse Mast Cell Protease 4 in the Formation and Degradation of Angiotensin II J. Biol. Chem., July 30, 2004; 279(31): 32339 - 32344. [Abstract] [Full Text] [PDF]

				C.-M. Hu, Y.-H. Chen, M.-T. Chiang, and L.-Y. Chau Heme Oxygenase-1 Inhibits Angiotensin II-Induced Cardiac Hypertrophy In Vitro and In Vivo Circulation, July 20, 2004; 110(3): 309 - 316. [Abstract] [Full Text] [PDF]

				Y. Nagashio, H. Asaumi, S. Watanabe, Y. Nomiyama, M. Taguchi, M. Tashiro, T. Sugaya, and M. Otsuki Angiotensin II type 1 receptor interaction is an important regulator for the development of pancreatic fibrosis in mice Am J Physiol Gastrointest Liver Physiol, July 1, 2004; 287(1): G170 - G177. [Abstract] [Full Text] [PDF]

				C Roncal, J Orbe, J.A Rodriguez, M Belzunce, O Beloqui, J Diez, and J.A Paramo Influence of the 4G/5G PAI-1 genotype on angiotensin II-stimulated human endothelial cells and in patients with hypertension Cardiovasc Res, July 1, 2004; 63(1): 176 - 185. [Abstract] [Full Text] [PDF]

				J. Hokamaki, H. Kawano, M. Yoshimura, H. Soejima, S. Miyamoto, I. Kajiwara, S. Kojima, T. Sakamoto, S. Sugiyama, N. Hirai, et al. Urinary biopyrrins levels are elevated in relation to severity of heart failure J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1880 - 1885. [Abstract] [Full Text] [PDF]

				B. Jiang, S. Xu, X. Hou, D. R. Pimentel, and R. A. Cohen Angiotensin II Differentially Regulates Interleukin-1-{beta}-inducible NO Synthase (iNOS) and Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression: ROLE OF p38 MAPK J. Biol. Chem., May 7, 2004; 279(19): 20363 - 20368. [Abstract] [Full Text] [PDF]

				Y. Chen, D. Lasaitiene, B. G. Gabrielsson, L. M.S. Carlsson, H. Billig, B. Carlsson, N. Marcussen, X.-F. Sun, and P. Friberg Neonatal Losartan Treatment Suppresses Renal Expression of Molecules Involved in Cell-Cell and Cell-Matrix Interactions J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1232 - 1243. [Abstract] [Full Text] [PDF]

				Y. Ishiyama, P. E. Gallagher, D. B. Averill, E. A. Tallant, K. B. Brosnihan, and C. M. Ferrario Upregulation of Angiotensin-Converting Enzyme 2 After Myocardial Infarction by Blockade of Angiotensin II Receptors Hypertension, May 1, 2004; 43(5): 970 - 976. [Abstract] [Full Text] [PDF]

				H. J. Han, S. H. Park, and Y. J. Lee Signaling cascade of ANG II-induced inhibition of {alpha}-MG uptake in renal proximal tubule cells Am J Physiol Renal Physiol, April 1, 2004; 286(4): F634 - F642. [Abstract] [Full Text] [PDF]

				A. Nishiyama, L. Yao, Y. Nagai, K. Miyata, M. Yoshizumi, S. Kagami, S. Kondo, H. Kiyomoto, T. Shokoji, S. Kimura, et al. Possible Contributions of Reactive Oxygen Species and Mitogen-Activated Protein Kinase to Renal Injury in Aldosterone/Salt-Induced Hypertensive Rats Hypertension, April 1, 2004; 43(4): 841 - 848. [Abstract] [Full Text] [PDF]

				J.-M. Li, S. Wheatcroft, L. M. Fan, M. T. Kearney, and A. M. Shah Opposing Roles of p47phox in Basal Versus Angiotensin II-Stimulated Alterations in Vascular O2- Production, Vascular Tone, and Mitogen-Activated Protein Kinase Activation Circulation, March 16, 2004; 109(10): 1307 - 1313. [Abstract] [Full Text] [PDF]

				A. Paul, K. W.S. Ko, L. Li, V. Yechoor, M. A. McCrory, A. J. Szalai, and L. Chan C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, February 10, 2004; 109(5): 647 - 655. [Abstract] [Full Text] [PDF]

				A. Nishiyama, M. Yoshizumi, H. Hitomi, S. Kagami, S. Kondo, A. Miyatake, M. Fukunaga, T. Tamaki, H. Kiyomoto, M. Kohno, et al. The SOD Mimetic Tempol Ameliorates Glomerular Injury and Reduces Mitogen-Activated Protein Kinase Activity in Dahl Salt-Sensitive Rats J. Am. Soc. Nephrol., February 1, 2004; 15(2): 306 - 315. [Abstract] [Full Text] [PDF]

				D. M. Nanus Of Peptides and Peptidases: The Role of Cell Surface Peptidases in Cancer Clin. Cancer Res., December 15, 2003; 9(17): 6307 - 6309. [Full Text] [PDF]

				L. Ferron, V. Capuano, Y. Ruchon, E. Deroubaix, A. Coulombe, and J.-F. Renaud Angiotensin II Signaling Pathways Mediate Expression of Cardiac T-Type Calcium Channels Circ. Res., December 12, 2003; 93(12): 1241 - 1248. [Abstract] [Full Text] [PDF]

				P. Trongtorsak, T. O Morgan, and L. M. Delbridge Combined renin-angiotensin system blockade and dietary sodium restriction impairs cardiomyocyte contractility Journal of Renin-Angiotensin-Aldosterone System, December 1, 2003; 4(4): 213 - 219. [Abstract] [PDF]

				M. G Friedrich, B. Dahlof, U. Sechtem, T. Unger, M. Knecht, R. Dietz, and TELMAR Investigators Telmisartan Effectiveness on Left ventricular MAss Reduction (TELMAR) as assessed by magnetic resonance imaging in patients with mild-to-moderate hypertension -- a prospective, randomised, double-blind comparison of telmisartan with metoprolol over a period of six months -- rationale and study design Journal of Renin-Angiotensin-Aldosterone System, December 1, 2003; 4(4): 234 - 243. [Abstract] [PDF]

				T.-H. Cheng, P.-Y. Cheng, N.-L. Shih, I.-B. Chen, D. L. Wang, and J.-J. Chen Involvement of reactive oxygen species in angiotensin II-induced endothelin-1 gene expression in rat cardiac fibroblasts J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1845 - 1854. [Abstract] [Full Text] [PDF]

				Y. Izumiya, S. Kim, Y. Izumi, K. Yoshida, M. Yoshiyama, A. Matsuzawa, H. Ichijo, and H. Iwao Apoptosis Signal-Regulating Kinase 1 Plays a Pivotal Role in Angiotensin II-Induced Cardiac Hypertrophy and Remodeling Circ. Res., October 31, 2003; 93(9): 874 - 883. [Abstract] [Full Text] [PDF]

				G. Perez de Lema, C. de Wit, C. D. Cohen, E. Nieto, A. Molina, B. Banas, B. Luckow, A. B. Vicente, F. Mampaso, and D. Schlondorff Angiotensin Inhibition Reduces Glomerular Damage and Renal Chemokine Expression in MRL/lpr Mice J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 275 - 281. [Abstract] [Full Text] [PDF]

				D. Iwanciw, M. Rehm, M. Porst, and M. Goppelt-Struebe Induction of Connective Tissue Growth Factor by Angiotensin II: Integration of Signaling Pathways Arterioscler. Thromb. Vasc. Biol., October 1, 2003; 23(10): 1782 - 1787. [Abstract] [Full Text] [PDF]

				A. Montanari, A. Biggi, N. Carra, M. Ziliotti, E. Fasoli, L. Musiari, P. Perinotto, and A. Novarini Endothelin-A Receptors Mediate Renal Hemodynamic Effects of Exogenous Angiotensin II in Humans Hypertension, October 1, 2003; 42(4): 825 - 830. [Abstract] [Full Text] [PDF]

				J.-Z. Zhang, L. Gao, M. Widness, X. Xi, and T. S. Kern Captopril Inhibits Glucose Accumulation in Retinal Cells in Diabetes Invest. Ophthalmol. Vis. Sci., September 1, 2003; 44(9): 4001 - 4005. [Abstract] [Full Text] [PDF]

				R. A. S. Santos, A. C. S. e Silva, C. Maric, D. M. R. Silva, R. P. Machado, I. de Buhr, S. Heringer-Walther, S. V. B. Pinheiro, M. T. Lopes, M. Bader, et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas PNAS, July 8, 2003; 100(14): 8258 - 8263. [Abstract] [Full Text] [PDF]

				D. S. Jacoby and D. J. Rader Renin-Angiotensin System and Atherothrombotic Disease: From Genes to Treatment Arch Intern Med, May 26, 2003; 163(10): 1155 - 1164. [Abstract] [Full Text] [PDF]

				C.-M. Cheng, H.-J. Hong, J.-C. Liu, N.-L. Shih, S.-H. Juan, S.-H. Loh, P. Chan, J.-J. Chen, and T.-H. Cheng Crucial Role of Extracellular Signal-Regulated Kinase Pathway in Reactive Oxygen Species-Mediated Endothelin-1 Gene Expression Induced by Endothelin-1 in Rat Cardiac Fibroblasts Mol. Pharmacol., May 1, 2003; 63(5): 1002 - 1011. [Abstract] [Full Text] [PDF]

				J.-M. Li and A. M. Shah Mechanism of Endothelial Cell NADPH Oxidase Activation by Angiotensin II. ROLE OF THE p47phox SUBUNIT J. Biol. Chem., March 28, 2003; 278(14): 12094 - 12100. [Abstract] [Full Text] [PDF]

				S. Takai, H. Sakonjo, K. Fukuda, D. Jin, M. Sakaguchi, K. Kamoshita, K. Ishida, Y. Sukenaga, and M. Miyazaki A Novel Chymase Inhibitor, 2-(5-Formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl]acetamide (NK3201), Suppressed Intimal Hyperplasia after Balloon Injury J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 841 - 844. [Abstract] [Full Text] [PDF]

				M. Boschmann, J. Jordan, F. Adams, N.-J. Christensen, J. Tank, G. Franke, M. Stoffels, A. M. Sharma, F. C. Luft, and S. Klaus Tissue-Specific Response to Interstitial Angiotensin II in Humans Hypertension, January 1, 2003; 41(1): 37 - 41. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, S. Articles by Iwao, H. Search for Related Content PubMed PubMed Citation Articles by Kim, S. Articles by Iwao, H.