Protection by Red Wine Polyphenols against Metabolic and Cardiovascular Alterations Associated with Obesity: A Possible Link with Estrogen Alpha Receptor

Epidemiological studies report an inverse association between dietary flavonoid consumption and mortality from cardiovascular and metabolic diseases. Red wine contains a wide variety of polyphenols (RWPC), which mainly derive from grape solids (skin and seeds) and can be divided into two classes, flavonoids and non-flavonoids. RWPC exert numerous effects including antioxidant and free radical properties, anti-platelet aggregating and anti-thrombotic activities. Moreover, RWPC are powerful vasodilators and contribute to the preservation of the integrity of the endothelium and to the inhibition of smooth muscle cell proliferation and migration. All these effects of red wine may interfere with atherosclerotic plaque development and stability, vascular thrombosis and occlusion and explain the prevention of ischemic heart disease, stroke and metabolic diseases observed in different experimental models. With regard to obesity, we studied the effects of dietary supplementation of RWPC in Zucker fatty rats (ZF). We show that RWPC lead to an improvement of glucose and lipid metabolism in ZF rats, enhances cardiac function and decreases peripheral resistance. In addition, RWPC improve endothelium-dependent relaxation in both aorta and small mesenteric arteries from ZF rats, an effect accompanied by an increase of vascular nitric oxide (NO) production and a decrease of superoxide anions release, resulting in an increase of NO bioavailability. Thus, RWPC lead to an overall improvement in obesity-associated alterations, including glucose and lipid metabolism, as well as endothelial and cardiac functions. A molecular basis of the effect of RWPC has been provided on the endothelium, indentifying the alpha isoform of the estrogen receptor (ERα) as the key receptor, or at least one of those transducing vascular effects exerted by these compounds, particularly delphinidin with respect to NO production. These results are of importance inasmuch as RWPC, by interacting with ERα, can activate other targets such the sirtuin-1-adenosine monophosphate protein kinase network, both of which are amongst the most potent regulators of cellular metabolism, including vascular cells, adipocytes and hepatocytes. Altogether, the available evidence indicates that RWPC might be of therapeutic benefit for cardiovascular and metabolic protections, although prospective controlled clinical trials are still needed