Resveratrol and Estradiol Rapidly Activate MAPK Signaling through Estrogen Receptors α and β in Endothelial Cells

Abstract

Vascular endothelial cells (EC)are an important target of estrogen action through both the classical genomic (i.e. nuclear-initiated) activities of estrogen receptors ␣ and ␤ (ER␣ and ER␤) and the rapid "nongenomic" (i.e. membrane-initiated) activation of ER that stimulates intracellular phosphorylation pathways. We tested the hypothesis that the red wine polyphenol trans-resveratrol activates MAPK signaling via rapid ER activation in bovine aortic EC, human umbilical vein EC, and human microvascular EC. We report that bovine aortic EC, human umbilical vein EC, and human microvascular EC express ER␣ and ER␤. We demonstrate that resveratrol and estradiol (E 2 ) rapidly activated MAPK in a MEK-1, Src, matrix metalloproteinase, and epidermal growth factor receptor-dependent manner. Importantly, resveratrol activated MAPK and endothelial nitric-oxide synthase (eNOS) at nM concentrations (i.e. an order of magnitude less than that required for ER genomic activity) and concentrations possibly achieved transiently in serum following oral red wine consumption. Co-treatment with ER antagonists ICI 182,780 or 4-hydroxytamoxifen blocked resveratrol-or E 2 -induced MAPK and eNOS activation, indicating ER dependence. We demonstrate for the first time that ER␣-and ER␤-selective agonists propylpyrazole triol and diarylpropionitrile, respectively, stimulate MAPK and eNOS activity. A red but not a white wine extract also activated MAPK, and activity was directly correlated with the resveratrol concentration. These data suggest that ER may play a role in the rapid effects of resveratrol in EC and that some of the atheroprotective effects of resveratrol may be mediated through rapid activation of ER signaling in EC.Epidemiological studies have indicated that the consumption of red wine reduces the incidence of mortality from coronary heart disease (CHD) 1 (1, 2). The cardioprotective effect has been attributed to the polyphenol fraction of red wine (1). A key polyphenol in red wine is resveratrol, trans-3,5,4Ј-trihydroxystilbene, from grape skin. Red wine contains 1-75 mg of transresveratrol/liter (3). Studies in male rats demonstrated that an alcohol-free red wine extract and resveratrol protect the heart from ischemia reperfusion injury (4). Rodent studies showed that orally administered resveratrol is absorbed in the gut, has high affinity for heart and liver (5, 6), and is metabolized to glucuronides that have a t1 ⁄2 of ϳ1.5 h (7). A recurrent question is whether resveratrol, at concentrations present in red wine, is effective in vivo. The oral absorption of 25 mg of trans-

Astragali Radix elicits anti-inflammation via activation of MKP-1, concomitant with attenuation of p38 and Erk

“…Polyphenolic compounds from various herbs have been found to work as phytoestrogens (Mitchell et al, 2000;Gong et al, 2003;Klinge et al, 2005), antioxidants (Rüfer and Kulling, 2006), tyrosine kinase inhibitors (Kousidou et al, 2006), and anti-inflammatory compounds (Jung et al, 2007). HPLC analysis of AR displayed the presence of several secondary metabolites such as polyphenolic flavonoids including formononetin (Fig.…”

Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat

“…Again, the following study suggests possible involvement of increased β-catenin translocation followed by VEGF expression in the resveratrol and combination groups after myocardial infarction which might be one of the positive effect of β-catenin and its angiogenic property that leads to chronic cardioprotection. From the literature β-catenin is found to be a critical mediator during development and angiogenesis [24], which is phosphorylated in a cytosolic multiprotein complex containing adenomatous polyposis coli protein (APC), Axin and GSK-3β [24][25][26][27]. When phosphorylation of β-catenin is blocked, this allows β-catenin to accumulate and translocate into nucleus, where it forms a complex with T-cell transcription factors/lymphoid-enhancer binding factor (TCF/LEF) family of transcription factors and is able to activate or repress several important target genes, such as c-Myc, cyclin D1, fibronectin, VEGF, Bcl-2 and survivin [28][29][30][31].…”

Variant estrogen receptor–c-Src molecular interdependence and c-Src structural requirements for endothelial NO synthase activation

“…Heterotrimeric G proteins including G␣i and G␤␥ have been shown to productively interact with ER␣ and promote E2-stimulated NO release (18,19). In some models, ER␣-dependent induction of eNOS can be driven by activation of matrix metalloproteinases, epidermal growth factor receptor activation, and consequent ERK MAP kinase activation cascades (20). Additionally, rapid responses to nonpeptide hormones other than E2, triggering a phosphatidylinositol 3-kinase/Akt-dependent …”