Reciprocal regulation of endothelin-1 and nitric oxide: Relevance in the physiology and pathology of the cardiovascular system

doi:10.1016/S0074-7696(01)09014-3

International Review of Cytology

Volume 209, 2001, Pages 241-272

https://doi.org/10.1016/S0074-7696(01)09014-3 Get rights and content

Abstract

The endothelium plays a crucial role in the regulation of cardiovascular structure and function by releasing several mediators in response to biochemical and physical stimuli. These mediators are grouped into two classes: (1) endothelium-derived constricting factors (EDCFs) and (2) endothelium-derived relaxing factors (EDCFs), the roles of which are considered to be detrimental and beneficial, respectively. Endothelin-1 (ET-1) and nitric oxide (NO) are the prototypes of EDCFs and EDCFs, respectively, and their effects on the cardiovascular system have been studied in depth. Numerous conditions characterized by an impaired availability of NO have been found to be associated with enhanced synthesis of ET-1, and vice versa, thereby suggesting that these two factors have a reciprocal regulation. Experimental studies have provided evidence that ET -1 may exert a bidirectional effect by either enhancing NO production via ETB receptors located in endothelial cells or blunting it via ET_A receptors prevalently located in the vascular smooth muscle cells. Conversely, NO was found to inhibit ET-1 synthesis in different cell types. In vitro and in vivo studies have started to unravel the molecular mechanisms involved in this complex interaction. It has been clarified that several factors affect in opposite directions the transcription of preproET-1 and NO-synthase genes, nuclear factor-κB and peroxisome proliferator-activated receptors playing a key role in these regulatory mechanisms. ET-1 and NO interplay seems to have a great relevance in the physiological regulation of vascular tone and blood pressure, as well as in vascular remodeling. Moreover, an imbalance between ET-1 and NO systems may underly the mechanisms involved in the pathogenesis of systemic and pulmonary hypertension and atherosclerosis.

References (196)

B. Battistini et al.
Growth regulatory properties of endothelins
Peptides
(1993)
K.F. Beck et al.
Endothelin-1 inhibits cytokine-stimulated transcription of inducible nitric oxide synthase in glomerular mesangial cells
Kidney Int.
(1995)
K.F. Beck et al.
Cloning and sequencing of the proximal promoter of the rat iNOS gene: Activation of NF-κB is not sufficient for transcription of the iNOS gene in rat mesangial cells
FEBS Lett.
(1996)
S.M. Bode-Boger et al.
Elevated L-arginine/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits
Biochem. Biophys. Res. Commun.
(1996)
R.H. Boger et al.
Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease
J. Am. Coll. Cardiol.
(1998)
H. Drexler et al.
Endothelial dysfunction in human disease
J. Mol. Cell Cardiol.
(1999)
N. Duerrschmidt et al.
Endothelin-I induces NAD(P)H oxidase in human endothelial cells
Biochem. Biophys. Res. Commun.
(2000)
S.J. Duffy et al.
Treatment of hypertension with ascorbic acid
Lancet
(1999)
J. Dupuis et al.
Reduced pulmonary clearance of endothelin-1 in pulmonary hypertension
Am. Heart J
(1998)
T. Emori et al.
Cellular mechanism of thrombin on endothelin-1 biosynthesis and release in bovine endothelial cell
Biochem. Soc. Trans.
(1992)

I. Fleming et al.

NO: The primary EDRE

J. Mol. Cell Cardiol.

(1999)

C. Gallois et al.

Role of NF-kB in the antiproliferative effect of endothelin-1 and tumor necrosis factor-alpha in human hepatic stellate cells. Involvement of cyclooxygenase-2

J. Biol. Chem.

(1998)

G.A. Gray et al.

The endothelin system and its potential as a therapeutic target in cardiovascular disease

Pharmacol. Ther.

(1996)

J.P. Hinson et al.

The relationship between adrenal vascular events and steroid secretion: The role of mastcells and endothelin

J. Steroid Biochem. Mol. Biol.

(1991)

A.K. Hughes et al.

Effect of reactive oxygen species on endothelin-1 production by human mesangial cells

Kidney Int.

(1996)

T. Ishizuka et al.

Endothelin-1 enhances vascular cell adhesion molecule-1 expression in tumor necrosis factor alpha-stimulated vascular endothelial cells

Eur J. Pharmacol.

(1999)

W. Kiowski et al.

Evidence for endothelin-l-mediated vasoconstriction in severe chronic heart failure

Lancet

(1995)

F. Kishi et al.

Novel 31-amino acid lenght endothelins cause constriction of vascular smooth muscle

Biochem. Biophys. Res. Commun.

(1998)

M. Kitakaze et al.

A Ca²⁺ channel blocker, benidipine, increases coronary blood flow and attenuates the severity of myocardial ischemia via NO-dependent mechanisms in dogs

J. Am. Coll. Cardiol.

(1999)

W. Aji et al.

l-arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice

Circulation

(1997)

S.E. Akopov

Nitric oxide (EDRF) enhances the vasorelaxing effect of dihydropyridine calcium antagonists in isolated human middle cerebral arteries

Methods Find. Exp. Clin. Pharmacol.

(1996)

G. Aliev et al.

Decreased constitutive nitric oxide synthase, but increased inducible nitric oxide synthase and endothelin-I immunoreactivity in aortic endothelial cells of Donryu rats on cholesterol-enriched diet

Anat. Rec.

(2000)

J. Alonso et al.

Endothelial cytosolic proteins bind to the 3′ untranslated region of endothelial nitric oxide synthase mRNA: Regulation by tumor necrosis factor alpha

Mol. Cell Biol.

(1997)

P.J. Andrew et al.

Enzymatic function of nitric oxide synthases

Cardiovasc. Res.

(1999)

J.L. Balligand et al.

Induction of NO synthase in rat cardiac microvascular endothelial cells by IL-1β and INF-gamma

Am. J. Physiol.

(1995)

J.D. Banting et al.

Acute hypertension after nitric oxide synthase inhibition is mediated primarily by increased endothelin vasoconstriction

J. Hypertens.

(1996)

G. Barer et al.

Endothelial control of the pulmonary circulation in normal and chronically hypoxic rats

J. Physiol. (London)

(1993)

M. Barton et al.

Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice

M. Barton et al.

Differential modulation of the renal and myocardial endothelin system by angiotensin II in vivo. Effects of chronic selective ETA receptor blockade

J. Cardiovasc. Pharmacol.

(1998)

A.S. Belloni et al.

Endothelin adrenocortical secretagogue effect is mediated by the B receptor in rats

Hypertension

(1996)

R. Berkels et al.

The calcium-antagonist nifedipine stimulates endothelial NO release in therapeutical concentrations

Pharmaceut. Pharmacol. Lett.

(1996)

P.J. Best et al.

Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental hypercholesterolemia in vitro

Arterioscler Thromb. Vasc. Biol.

(1999)

A.S. Bilsel et al.

17β-Estradiol modulates endothelin-1 expression and release in human endothelial cells

Cardiovasc. Res.

(2000)

D. Bishop-Bailey

Peroxisome proliferator-activated receptors in the cardiovascular system

Br. J. Pharmacol.

(2000)

K.D. Bloch

Regulation of endothelial NO synthase mRNA stability: RNA-binding proteins crowd on the 3'-untranslated region

Circ. Res.

(1999)

S.M. Bode-Boger et al.

l-Arginine induces nitric oxide-dependent vasodilation in patients with critical limb ischemia. A randomized, controlled study

Circulation

(1996)

S.M. Bode-Boger et al.

l-Arginine infusion decreases peripheral arterial resistance and inhibiits platelet aggregation in healthy subjects

Clin. Sci.

(1994)

C. Boulanger et al.

Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide

J. Clin. Invest.

(1990)

R.P. Brandes et al.

An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice

D.S. Bredt et al.

Nitric oxide: A physiologic messenger molecule

Annu. Rev. Biochem.

(1994)

M. Browatzki et al.

Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-κB in human vascular smooth muscle cells

Basic Res. Cardiol.

(2000)

K.W. Buchan et al.

PPAR agonists as direct modulators of the vessel wall in cardiovascular disease

Med. Res. Rev.

(2000)

J.C.J. Burnett

Coronary endothelial dysfunction in the hypertensive patient: From myocardial ischemia to heart failure

J. Hum. Hypertens.

(1997)

G. Burnstock

Release of vasoactive substances from endothelial cells by shear stress and purinergic mechanosensory transduction

J. Anat.

(1999)

L.D. Buttery et al.

Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite

Lab. Invest.

(1996)

A.I. Campbell et al.

Cell-based gene transfer to the pulmonary vasculature: Endothelial nitric oxide synthase overexpression inhibits monocrotaline-induced pulmonary hypertension

Am. J. Respir Cell Mol. Biol.

(1999)

C. Cardillo et al.

Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo

Hypertension

(2000)

Y.F. Chen et al.

Endothelin and pulmonary hypertension

J. Cardiovasc. Pharmacol.

(2000)

T.H. Cheng et al.

Reactive oxygen species modulate endothelin-I-induced c-fos gene expression in cardiomyocytes

Cardiovasc. Res.

(1999)

J.P. Cooke

Is atherosclerosis an arginine defiency disease?

J. Investig. Med.

(1998)

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In general, ET-1 keeps delicate balance in cells, only when it is overexpressed, it will lead to hypertension and cardiovascular disease. The interaction of NO and ET-1 seems to have a great correlation in the regulation of blood pressure and vascular tone, which may be related to the pathogenesis of atherosclerosis [31]. In the present study, the level of NO was significantly (p < 0.
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Reciprocal regulation of endothelin-1 and nitric oxide: Relevance in the physiology and pathology of the cardiovascular system

Abstract

Peptides

Kidney Int.

FEBS Lett.

Biochem. Biophys. Res. Commun.

J. Am. Coll. Cardiol.

J. Mol. Cell Cardiol.

Biochem. Biophys. Res. Commun.

Lancet

Am. Heart J

Biochem. Soc. Trans.

J. Mol. Cell Cardiol.

J. Biol. Chem.

Pharmacol. Ther.

J. Steroid Biochem. Mol. Biol.

Kidney Int.

Eur J. Pharmacol.

Lancet

Biochem. Biophys. Res. Commun.

J. Am. Coll. Cardiol.

l-arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice

Circulation

Nitric oxide (EDRF) enhances the vasorelaxing effect of dihydropyridine calcium antagonists in isolated human middle cerebral arteries

Methods Find. Exp. Clin. Pharmacol.

Decreased constitutive nitric oxide synthase, but increased inducible nitric oxide synthase and endothelin-I immunoreactivity in aortic endothelial cells of Donryu rats on cholesterol-enriched diet

Anat. Rec.

Endothelial cytosolic proteins bind to the 3′ untranslated region of endothelial nitric oxide synthase mRNA: Regulation by tumor necrosis factor alpha

Mol. Cell Biol.

Enzymatic function of nitric oxide synthases

Cardiovasc. Res.

Induction of NO synthase in rat cardiac microvascular endothelial cells by IL-1β and INF-gamma

Am. J. Physiol.

Acute hypertension after nitric oxide synthase inhibition is mediated primarily by increased endothelin vasoconstriction

J. Hypertens.

Endothelial control of the pulmonary circulation in normal and chronically hypoxic rats

J. Physiol. (London)

Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice

Differential modulation of the renal and myocardial endothelin system by angiotensin II in vivo. Effects of chronic selective ETA receptor blockade

J. Cardiovasc. Pharmacol.

Endothelin adrenocortical secretagogue effect is mediated by the B receptor in rats

Hypertension

The calcium-antagonist nifedipine stimulates endothelial NO release in therapeutical concentrations

Pharmaceut. Pharmacol. Lett.

Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental hypercholesterolemia in vitro

Arterioscler Thromb. Vasc. Biol.

17β-Estradiol modulates endothelin-1 expression and release in human endothelial cells

Cardiovasc. Res.

Peroxisome proliferator-activated receptors in the cardiovascular system

Br. J. Pharmacol.

Regulation of endothelial NO synthase mRNA stability: RNA-binding proteins crowd on the 3'-untranslated region

Circ. Res.

l-Arginine induces nitric oxide-dependent vasodilation in patients with critical limb ischemia. A randomized, controlled study

Circulation

l-Arginine infusion decreases peripheral arterial resistance and inhibiits platelet aggregation in healthy subjects

Clin. Sci.

Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide

J. Clin. Invest.

An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice

Nitric oxide: A physiologic messenger molecule

Annu. Rev. Biochem.

Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-κB in human vascular smooth muscle cells

Basic Res. Cardiol.

PPAR agonists as direct modulators of the vessel wall in cardiovascular disease

Med. Res. Rev.

Coronary endothelial dysfunction in the hypertensive patient: From myocardial ischemia to heart failure

J. Hum. Hypertens.

Release of vasoactive substances from endothelial cells by shear stress and purinergic mechanosensory transduction

J. Anat.

Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite

Lab. Invest.

Cell-based gene transfer to the pulmonary vasculature: Endothelial nitric oxide synthase overexpression inhibits monocrotaline-induced pulmonary hypertension

Am. J. Respir Cell Mol. Biol.

Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo

Hypertension

Endothelin and pulmonary hypertension

J. Cardiovasc. Pharmacol.

Reactive oxygen species modulate endothelin-I-induced c-fos gene expression in cardiomyocytes

Cardiovasc. Res.

Is atherosclerosis an arginine defiency disease?