Resveratrol Improves Vascular Function in Patients With Hypertension and Dyslipidemia by Modulating NO Metabolism

Abstract

Abstract-Epidemiological studies have demonstrated that the Mediterranean diet, which is rich in resveratrol, is associated with a significantly reduced risk of cardiovascular disease. However, the molecular mechanisms that underlie the beneficial effects of resveratrol on cardiovascular function remain incompletely understood. Therefore, we set out to identify the molecular target(s) mediating the protective action of resveratrol on vascular function. To this end, we performed vascular reactivity studies to evaluate the effects of resveratrol on superior thyroid artery obtained from 59 patients with hypertension and dyslipidemia. We found that resveratrol evoked vasorelaxation and reduced endothelial dysfunction through the modulation of NO metabolism via (1) an 5′ adenosine monophosphate-activated protein kinase-mediated increase in endothelial NO synthase activity; (2) a rise in tetrahydrobiopterin levels, which also increases endothelial NO synthase activity; and (3) attenuation of vascular oxidative stress, brought about by overexpression of manganese superoxide dismutase via an nuclear factor erythroid-derived 2-like 2-dependent mechanism. The effects of resveratrol on acetylcholine vasorelaxation were also tested in vessels from patients with nonhypertensive nondyslipidemia undergoing thyroid surgery. In this setting, resveratrol failed to exert any effect. Thus, our finding that resveratrol reduces endothelial dysfunction, an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular disease, supports the concept that the risk of vascular events could be further reduced by adherence to a set of dietary and behavioral guidelines. MethodsFor detailed methodology, please see the online-only Data Supplement. In brief, we collected superior thyroid artery (STA) from patients with HD (Table). Each vessel was divided into rings for use in different experimental series. Some rings were treated with resveratrol at 37°C, and then proteins were rapidly extracted for molecular studies to evaluate total and phosphorylated endothelial NO synthase (eNOS) protein levels, eNOS dimerization, GTP cyclohydrolase 1, copper-zinc superoxide dismutase (Cu-ZnSOD) and MnSOD expression, and NRF2 translocation; other rings were kept in 4°C Krebs solution for vascular reactivity studies; some were used for highperformance liquid chromatography (HPLC) dosage of BH 4 ; and others were rapidly used for measurement of O 2 − . Studies were also performed on vessels removed from patients with nonhypertensive, nondyslipidemia (nHD) undergoing thyroid surgery. Results Resveratrol Exerts a Vasorelaxant Effect by Modulating the Phosphorylation Status of eNOS and NO ReleaseEvaluation of the vascular reactivity of ex vivo STA from patients with HD revealed that endothelially mediated (acetylcholine-evoked) vasorelaxation was significantly blunted compared with relaxation induced by nitroglycerin ( Figure 1A). However, when HD STA rings were preconstricted with phenylephrine, resveratrol was ca...

Consumption of a Western-style diet during pregnancy impairs offspring islet vascularization in a Japanese macaque model

“…Previous studies have demonstrated that resveratrol supplementation improves vascular function and induces vasodilation (16,34,56). Although human studies have not yet assessed the safety or efficacy of resveratrol treatment during pregnancy in women consuming a WSD, our group demonstrated recently in our NHP model of WSD consumption during pregnancy that supplementation improved placental blood flow, consistent with its role in enhancing vascular function (52).…”

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

“…In addition to the involvement of SIRT1 and AMPK in mediating the endotheliumdependent vasodilatory effects of resveratrol, resveratrol has been shown to enhance NOS activity by increasing tetrahydrobiopterin (BH4) levels, a cofactor necessary for proper function of NOS [55]. The endothelium-dependent vasodilatory effect of resveratrol has also been attributed to the anti-oxidant properties of resveratrol [41,56].…”

The Gastrointestinal Tract: an Initial Organ of Metabolic Hypertension?

“…Resveratrol, a natural polyphenol in grapes and red wine, has been shown to have beneficial effects on glucose and lipid metabolism, vascular function, and antioxidative properties [111,112]. A Mediterranean diet rich in resveratrol is associated with a significantly reduced risk of cardiovascular diseases [113]. Therefore, increasing healthy dietary factors and preventing harmful dietary intake through the gastrointestinal tract are key steps for the prevention of metabolic hypertension.…”