Review ArticleHeart failure: how important is cellular sequestration? The role of the renin–angiotensin–aldosterone system
Introduction
Heart failure described as a pathologic process characterized by a decrease of contractility and consequent decline of cardiac output involves a complex set of changes like the release of inflammatory cytokines, endothelin, angiotensin II (Ang II) and aldosterone [1] which reprogram the cardiac muscle at cellular and molecular levels [2]. Moreover, defects in calcium-handling proteins [3], [4], enhanced oxidative stress [5] or apoptosis [6] are certainly involved.
A fundamental question remains: how important is cellular sequestration for the decline of ventricular function? In this context, sequestration here is defined as a myocyte isolation from the heart cell community. It is conceivable that a suppression of cell coupling as well as the isolation of a large number of heart cells elicited by interstitial fibrosis and rupture of cell contacts reduces appreciably the number of cardiomyocytes that participate in the contraction process. In the present review, I discuss the role of cellular sequestration in the failing heart emphasizing the abnormalities of intercellular communication and inward calcium current (ICa). Furthermore, I present evidence that the renin–angiotensin–aldosterone system plays an important role on cellular sequestration.
It is known that myocytes from the failing heart present several abnormalities of ion pumps, calcium reuptake from the sarcoplasmic reticulum, alteration of hormone receptors, ionic channels, etc. [7]. In cardiomyopathic hamsters, which are a good model of cardiomyopathy and heart failure in humans [8], there is calcium overload which has been considered a possible etiologic factor. Although the mechanism of this overload is not completely clear, there is evidence that the calcium uptake is enhanced [9] leading to a calcium-determined necrotic process with myocytolysis and fibrillar disarray [10]. In humans, calcium overload of the failing heart is secondary to a change in the [Na]i homeostasis (see Ref. [11]).
It is known that changes in ventricular structure play an important role in this pathologic condition. In heart failure with sudden death, for instance, alterations in microscopic anatomy involving cardiomyocyte hypertrophy, apoptosis, fibroblast hyperplasia, diffuse and focal matrix protein accumulation and recruitment of inflammatory cells are involved in abnormalities of impulse conduction and arrhythmias [12], [13]. The establishment of extensive areas of interstitial fibrosis and cell death leads to physiologic and morphologic disorganization of the failing ventricle which includes a reduced number of available myocytes for the contraction process and impairment of electrical synchronization.
Section snippets
Cell coupling is impaired in the failing heart
The electrical desynchronization seen in the failing heart is not only the result of cell isolation caused by interstitial fibrosis but also involves a decline in the process of intercellular communication. Indeed, an appreciable reduction of gap junction (gj) conductance has been described in the failing heart of cardiomyopathic hamsters, particularly at advanced stages of the disease [14]. Measurements of junctional conductance performed in cell pairs isolated from the failing ventricle of
Impaired function of sympathetic nervous system
It is known that the failing heart becomes insensitive to sympathetic stimulation [19] in part not only due to downregulation of beta adrenergic receptors but also related to a defective coupling of G-proteins to adenyl cyclase [19]. An increase in the alpha subunit of the inhibitory G-protein was confirmed by pertussis toxin-catalyzed ADP ribosylation [20]. Moreover, myocardial Gi mRNA levels are elevated in terminal cardiac failure [20].
Studies on the influence of beta adrenergic receptor
Renin–angiotensin system, intercellular signaling and heart failure
Although contraction is the most important function of the heart, one cannot forget that the heart is a complex electrochemical machine in which generation of electrical propagated responses is essential for the trigger of the contractile process. An increase in resistance of the gj to electrical current flow can result in the impairment of impulse propagation and cardiac arrhythmias [25]. Moreover, the suppression of cell communication reduces heart contractions by sequestering a large number
Ang II, cell coupling and growth: an important relationship?
Cell-to-cell communication occurs through hormones, cytokines and growth factors, which are released into the bloodstream or through local generation and responses to several ions and molecules, such as growth factors, nitric oxide, calcium ions or cytokines.
The exchange of second messengers and other signal molecules, which are involved in cell proliferation and function, take place through gj, which make possible the electrical synchronization of cardiac myocytes [26] and the metabolic
Is there a cardiac renin–angiotensin system in the failing heart?
There is some controversy concerning the synthesis of some components of the renin–angiotensin system inside the heart cell. The levels of cardiac renin, for instance, are extremely low in nephrectomized animals [46], suggesting that cardiac renin in the normal heart is dependent on its uptake from plasma [47]. However, using subcellular fractionation techniques Peters et al. [48] found that the majority of cardiac renin is located intracellularly. Moreover, in the adult rat heart an
On the possible role of endogenous Ang II on heart cell communication
The possible internalization of prorenin and the formation of renin inside the cardiac myocyte under pathologic conditions might lead to two possible consequences: formation of Ang II inside the cell [48] with consequent intracellular action of the peptide [14] or release of renin to the extracellular medium and formation of Ang II outside the cell with activation of AT1 receptors.
It is then conceivable that if Ang I is formed inside the cardiomyocyte, the administration of enalaprilat into the
ACE inhibitors, electrical synchronization and antiarrhythmic action
Conceivably, the decline of intercellular coupling caused by Ang II increases the intracellular resistance with consequent impairment of impulse propagation. Studies performed on rat papillary muscle of normal rats indicated that the peptide decreases the conduction velocity, while enalapril reduces the internal resistance and enhances the conduction velocity [70]. The improvement of impulse conduction produced by the acute administration of the ACE inhibitor is related to: (a) an increase in
Ang II and cardiac fibroblasts
The persistent activation of the renin–angiotensin system and the increment in the cardiac levels of Ang II leads to remodeling of the gj [26] and interstitial fibrosis. Studies of Booz and Baker [71] showed that chronic infusion of Ang II induces fibrosis, an effect reduced by AT1 receptor antagonists or ACE inhibitors. The activation of AT1 receptors in fibroblasts activates MAPKs and the JAK/STAT pathways with consequent increased expression of angiotensinogen and fibrosis-related proteins
Fibrosis and aldosterone: aldosterone–Ang II interaction
The presence of aldosterone receptors in cardiac muscle [77] and the evidence that the heart can synthesize aldosterone lead to the conclusion that aldosterone plays an important role in cardiac function. Adverse effects of aldosterone include interstitial fibrosis, congestive heart failure and cardiac arrhythmias.
It is well known that Ang II releases aldosterone from adrenal gland. The obvious question is how influential is aldosterone on the effects of Ang II? Recent studies indicated that in
Effect of intracellular and extracellular Ang II on the ICa
In cardiomyocytes of adult rats, in which Ang II has a negative inotropic action, the intracellular administration of the peptide reduced the ICa, whereas in normal hamsters, in which the peptide elicit a positive inotropic action, the intracellular administration of Ang II increased the ICa [84]. Similar result was found when Ang II was applied extracellularly. Stimulation of ICa by exogenous cAMP or inhibition of PKC did not alter the effect of intracellular Ang II on ICa but zaprinast, an
Local renin–angiotensin system and remodeling
Changes in cardiac gene expression and activation of the local renin–angiotensin system might be implicated in ventricular remodeling. In isolated and perfused rat heart the increase of coronary perfusion pressure and consequent stretch increased the steady state c-fos mRNA expression 2.3-fold [85]. Mechanical stretch also enhanced the expression of renin and angiotensinogen genes [86], [87] with the consequent increase of cardiac Ang II levels and remodeling. Recently, it was found that there
ACE2: possible implications for heart functions
ACE2 is a new enzyme with high homology to ACE [89], [90] and the ability to change Ang II into Ang 1–7 [91], [92]. Northern blot analysis showed ACE2 gene expression in heart, kidney and testes [93]. Immunochemical studies demonstrated ACE2 mainly in the endothelium of cardiac vessels [94]. As Ang 1–7 counteract the effects of Ang II [92], [94] and reduce the incidence of cardiac arrhythmias during ischemia–reperfusion [95], it is possible that Ang 1–7 be of therapeutic interest for heart
Conclusion
The activation of the cardiac renin–angiotensin–aldosterone system during the process of heart failure induces cellular sequestration by promoting remodeling of the gj and interstitial fibrosis. Therefore, the establishment of slow conduction pathways facilitates the generation of cardiac arrhythmias. The presence of aldosterone receptors and the enhanced production of the hormone in the failing heart indicates that aldosterone is an important factor involved in heart pathology. Evidence is
Acknowledgements
I want to thank Mrs. Maria Gonzalez for the technical work and the American Heart Association and NIH (HL-34148; GM 61838) for support.
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2013, International Journal of CardiologyCitation Excerpt :These findings indicate that BMSCs are potential candidates for the treatment of ischemic disease. Systemic activation of the renin–angiotensin system (RAS) is the hallmark of severe cardiovascular disease, such as heart failure [9] and MI [10]. In patients with hypertension, advanced atherosclerosis, or heart failure, the plasma level of angiotensinogen increases.
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2011, Regulatory PeptidesCitation Excerpt :As expected, the decrease of gap junction conductance leads to generation of electrical uncoupling and mechanical desynchronization [13,20]. These findings lead to the concept that the intracrine renin angiotensin system can be then considered an important component of the local renin angiotensin aldosterone system and might be involved in the generation cellular hypertrophy [22] and cardiac arrhythmias [9,13,60]. Non cardiac cells engineered to synthesize angiotensin II in absence of Ang II secretion, for instance, showed increased proliferation [99].
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2010, PeptidesCitation Excerpt :The classical renin–angiotensin system (RAS) is conceptualized as an enzymatic cascade in which renin derived from the juxtaglomerular cells of the kidney, acts on angiotensinogen originated from the liver generating angiotensin I which is converted to angiotensin II by the angiotensin converting enzyme (ACE) (see Fig. 1). Ang II plays a major role in blood pressure regulation, water-electrolyte balance and pathological remodeling of the heart [9]. Recent studies indicated that there is a local renin–angiotensin system in the heart and that Ang II generated locally may function inside the cell exerting an intracrine effect or have an autocrine or paracrine actions [6,27].