Estrogen receptor alpha as a key target of red wine polyphenols action on the endothelium
BACKGROUND: A greater reduction in cardiovascular risk and vascular protection associated with diet rich in polyphenols are generally accepted; however, the molecular targets for polyphenols effects remain unknown. Meanwhile evidences in the literature have enlightened, not only structural similarities between estrogens and polyphenols known as phytoestrogens, but also in their vascular effects. We hypothesized that alpha isoform of estrogen receptor (ERalpha) could be involved in the transduction of the vascular benefits of polyphenols. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used ERalpha deficient mice to show that endothelium-dependent vasorelaxation induced either by red wine polyphenol extract, Provinols, or delphinidin, an anthocyanin that possesses similar pharmacological profile, is mediated by ERalpha. Indeed, Provinols, delphinidin and ERalpha agonists, 17-beta-estradiol and PPT, are able to induce endothelial vasodilatation in aorta from ERalpha Wild-Type but not from Knock-Out mice, by activation of nitric oxide (NO) pathway in endothelial cells. Besides, silencing the effects of ERalpha completely prevented the effects of Provinols and delphinidin to activate NO pathway (Src, ERK 1/2, eNOS, caveolin-1) leading to NO production. Furthermore, direct interaction between delphinidin and ERalpha activator site is demonstrated using both binding assay and docking. Most interestingly, the ability of short term oral administration of Provinols to decrease response to serotonin and to enhance sensitivity of the endothelium-dependent relaxation to acetylcholine, associated with concomitant increased NO production and decreased superoxide anions, was completely blunted in ERalpha deficient mice. CONCLUSIONS/SIGNIFICANCE: This study provides evidence that red wine polyphenols, especially delphinidin, exert their endothelial benefits via ERalpha activation. It is a major breakthrough bringing new insights of the potential therapeutic of polyphenols against cardiovascular pathologies.
En este estudio de muestra como el receptor alpha del estrógeno juega un importante papel en la ruta metabólica en la cual los compuestos químicos denominados polifenoles y los cuales están presentes en el vino tinto ayudan a reducir el riesgo de enfermedades vasculares. Aquellos ratones carentes de este receptor no son capaces de usar los polifenoles para incrementar la producción de óxido nítrico.
We are continually learning more of the mechanisms by which polyphenols present in wine and certain other beverages act to improve vascular function. This report is valuable in that it demonstrates quite clearly that estrogen receptor alpha plays an important, perhaps the most important, role in the metabolic pathway by which these polyphenols help reduce the risk of vascular disease. Mice bred to be without these estrogen receptors could not utilize polyphenols to increase nitric oxide production that leads to relaxation of blood vessels. Also, when this estrogen receptor was blocked in normal mice, there was no improvement in vascular function from these polyphenols. The findings from this paper provide important new mechanisms by which wine and other sources of polyphenols may prevent cardiovascular disease.