Role of AMP-activated Protein Kinase in NO- and EDHF-mediated Endothelium-dependent Relaxations to Red Wine Polyphenols.

BACKGROUND: Several epidemiological studies have shown that regular consumption of moderate amounts of wine, in particular red wine, is associated with a decreased total mortality due, in part, to a reduced risk of cardiovascular diseases. The protective effect has been attributable to polyphenols, which are potent vasodilators and have anti-thrombotic properties. Polyphenols have been shown to induce pronounced endothelium-dependent relaxations of arteries by causing the redox-sensitive PI3-kinase-dependent formation of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). The aim of the present study was to determine the role of the AMP-activated protein kinase (AMPK) in the red wine polyphenols (RWPs)-induced endothelial formation of NO and EDHF. METHODS AND RESULTS: Vascular reactivity was assessed in organ chambers. Cultured porcine coronary artery endothelial cells porcine coronary artery segements were used to study the phosphorylation level of endothelial NO synthase (eNOS) at serine 1177, and AMPK at the Threonine 172 by Western blot analysis and immunohistochemical staining. RWPs caused endothelium-dependent relaxations in rings from rat aorta and mesenteric artery, and in those from porcine coronary artery. NO-mediated relaxations to RWPs as assessed in the presence of indomethacin and charybdotoxin plus apamin, were inhibited by compound C (an inhibitor of AMPK). Compound C also reduced EDHF-mediated relaxations as assessed in the presence of indomethacin and N(G)-nitro L-arginine. In contrast, compound C did not affect endothelium-dependent relaxations to acetylcholine and those to sodium nitroprusside. Moreover, RWPs induced the phosphorylation of AMPK at threonine 172 and eNOS at serine 1177 in endothelial cells; these responses were inhibited by compound C. CONCLUSION: The present findings indicate that RWPs cause both NO and EDHF-mediated relaxations in several types of isolated arteries and that these effects are dependent on the activation of the AMP-activated protein kinase pathway.

Angiotensin II induces the vascular expression of VEGF and MMP-2 in vivo: preventive effect of red wine polyphenols.

OBJECTIVE: Previous investigations have indicated that angiotensin II (Ang II)-induced hypertension and endothelial dysfunction are prevented by intake of red wine polyphenols (RWPs). Ang II has also been shown to increase the expression of VEGF and MMP-2, two major pro-inflammatory factors, in vascular diseases. Therefore, the aim of the present study was to determine whether intake of RWPs is able to prevent these effects in rats and, if so, to characterize the underlying mechanism. METHODS: VEGF and endothelial NO synthase (eNOS) expression was assessed by immunofluorescence and Western blotting, MMP-2 activity by zymography, and reactive oxygen species (ROS) formation by dihydroethidine. RESULTS: Ang II increased VEGF expression and MMP-2 activity in the aortic wall. Ang II-induced MMP-2 activation is inhibited by N(G)-nitro-L-arginine and MnTMPyP. Ang II increased the expression of eNOS, the formation of ROS and the nitration of proteins. The stimulatory effects of Ang II on these factors are prevented by RWPs intake. CONCLUSIONS: Infusion of Ang II induced vascular expression of VEGF and peroxynitrite-dependent activation of MMP-2, with both effects being prevented by RWPs intake. Thus, prevention of VEGF and MMP-2 expression might be involved in the protective effect of red wine on coronary heart diseases.

Dyslipidemia, obesity and other cardiovascular risk factors in the adult population in Senegal.

INTRODUCTION: According to the WHO, 50% of deaths worldwide (40.1% in developing countries) are due to chronic non-communicable diseases (NCDs). Of these chronic NCDs, cardiovascular diseases remain the leading cause of death and disability in developed countries. The Framingham study has shown the importance of hypercholesterolemia as a primary risk factor. In Senegal, the epidemiology of dyslipidemia and obesity are still poorly understood due to the lack of comprehensive studies on their impact on the general population. This motivated this study to look into the key epidemiologic and socio-demographic determinants of these risk factors. METHODS: It was a cross-sectional descriptive epidemiological survey which included 1037 individuals selected by cluster sampling. Data were collected using a questionnaire following the WHO STEPwise approach. Socio-demographic, health and biomedical variables were collected. P value <0.05 was considered to be statistically significant. RESULTS: The average age was 48 years with a female predominance (M: F of 0.6). The literacy rate was 65.2% and 44.7% of participants were from rural areas. The prevalence of hypercholesterolemia, hyperLDLemia, hypoHDLemia, hypertriglyceridemia and mixed hyperlipidemia were 56%, 22.5%, 12.4%, 7.11% and 1.9% respectively. One in four was obese (BMI> 30kg/m2) and 34.8% had abdominal obesity. The main factors significantly associated with dyslipidemia were obesity, urban dwelling, physical inactivity and a family history of dyslipidemia. CONCLUSION: The prevalence of dyslipidemia, obesity and other risk factors in the population was high needing immediate care for those affected and implementation of prevention strategies.

Role of gender and estrogen receptors in the rat aorta endothelium-dependent relaxation to red wine polyphenols.

Regular intake of moderate amounts of beverages rich in polyphenols such as red wine is associated with a protective effect on the vascular system, in part, by increasing the endothelial formation of nitric oxide (NO), a major vasoprotective factor. Since estrogens are potent inducers of NO formation and polyphenols have been shown to have phytoestrogen properties, we determined whether estrogen receptors mediate the stimulatory effect of red wine polyphenols (RWPs) on the endothelial formation of NO using isolated rat aortic rings and cultured endothelial cells. RWPs caused endothelium-dependent relaxations, which were more pronounced in the aorta of female than male rats. Increased relaxations were also observed to acetylcholine but not to sodium nitroprusside. Relaxations to RWPs were abolished by nitro l-arginine and MnTMPyP, markedly reduced by polyethyleneglycol-catalase and wortmannin, and not affected by the estrogen antagonist ICI 182,780 in aortic rings from males and females. eNOS expression was higher in aortic sections of female than male rats. RWPs caused the phosphorylation of Akt and eNOS in endothelial cells, which was unaffected by ICI 182,780. Thus, RWPs cause redox-sensitive PI3-kinase/Akt-dependent NO-mediated relaxations, which are more pronounced in the aorta of female than male rats; an effect most likely due to the increased expression level of eNOS rather than activation of estrogen receptors.