Inhibition of Cyclic Strain-Induced Endothelin-1 Gene Expression by Resveratrol

Abstract

Abstract-Resveratrol is a phytoestrogen naturally found in grapes and is among the major constituents of wine thought to have a cardioprotective effect. Endothelin-1 (ET-1) is a potent vasopressor synthesized by endothelial cells both in culture and in vivo. The aims of this study were to test the hypothesis that resveratrol may alter strain-induced ET-1 gene expression and to identify the putative underlying signaling pathways in endothelial cells. We show that resveratrol indeed potently inhibits strain-induced ET-1 secretion, ET-1 mRNA level, and ET-1 promoter activity. Resveratrol also inhibits strain-increased NADPH oxidase activity, reactive oxygen species formation, and extracellular signal-regulated kinases1/2 (ERK1/2) phosphorylation. Furthermore, pretreating cells with resveratrol or antioxidant N-acetyl-cysteine decreases strain-increased or hydrogen peroxide-increased ET-1 secretion, ET-1 promoter activity, and ET-1 mRNA and ERK1/2 phosphorylation. Using both the electrophoretic mobility shift assay and a reporter gene assay, resveratrol and N-acetyl-cysteine also attenuated the strain-stimulated activator protein-1 binding activity and activator protein-1 reporter activity. In summary, we demonstrate for the first time that resveratrol inhibits strain-induced ET-1 gene expression, partially by interfering with the ERK1/2 pathway through attenuation of reactive oxygen species formation. Thus, this study provides important new insights in the molecular pathways that may contribute to the proposed beneficial effects of resveratrol in the cardiovascular system. any epidemiological studies show a correlation between a low incidence of coronary heart disease and atherosclerosis and a moderate consumption of red wine. 1,2 The vasoprotective effect of red wine, also known as the "French paradox," is currently best exemplified by transresveratrol (trans-3,5,4Ј-hydroxystilbene). 3,4 Resveratrol has many biological activities, including protection from or reduction of the incidence of coronary heart disease. Resveratrol also has been found to protect the heart from ischemiareperfusion injury. 5 Antioxidant properties of resveratrol appear to be partly responsible for this activity. 5-9 Moreover, resveratrol was shown to relax aortic rings in rats through an endothelium-mediated enhancement of the nitric oxide (NO)-cGMP cascade. 10 Subsequent pharmacological studies indicate a direct relaxant effect of resveratrol on vascular smooth muscle that may exert beneficial effects in cardiovascular disease, though the mechanism of these effects is no known. 11 Recently, Orallo et al 12 demonstrated that the characteristic endothelium-dependent vasorelaxant effect of resveratrol in the rat aorta appeared to be caused by the inhibition of vascular NADH/NADPH oxidase and the subsequent decrease in the generation of basal cellular superoxide anions and, therefore, of NO biotransformation. However, little is known about the cellular/molecular mechanisms whereby resveratrol could protect against coronary heart disease. Indee...

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Protective mechanisms of resveratrol against ischemia-reperfusion-induced damage in hearts obtained from Zucker obese rats: the role of GLUT-4 and endothelin

“…Resveratrol may reduce the expression of ET, leading to the reduction of ET production. It is of interest to note that the effect of resveratrol was not directly connected with various ET receptor blockades in endothelial and myocardial cells, but resveratrol significantly inhibited strain-induced ET mRNA level, protein expression, and promoter activity (30). In additional studies, it was also proven that resveratrol inhibited angiotensin II-induced cell proliferation and ET expression (8), which is related to the phosphorylation of angiotensin IIinduced extracellular signal regulated kinase activity.…”

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