Resveratrol Suppresses Angiotensin II-Induced Akt/Protein Kinase B and p70 S6 Kinase Phosphorylation and Subsequent Hypertrophy in Rat Aortic Smooth Muscle Cells

Abstract

Resveratrol (RV), a polyphenolic substance found in grape skin, is proposed to account in part for the protective effect of red wine in the cardiovascular system. Angiotensin II (Ang II)-induced hypertrophy of vascular smooth muscle cells (VSMCs) is a pivotal step in the development of cardiovascular disease. The aims of this study were to test the hypothesis that RV may alter Ang II-mediated hypertrophic VSMC growth and to identify the putative underlying signaling pathways. We show that RV indeed potently inhibits Ang II-induced [ 3 H]leucine incorporation in a concentration-dependent manner (50 M RV, 71% inhibition). Western blot analysis reveals that phosphorylation of Akt/protein kinase B (PKB) and to a lesser extent the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) 1/2, both essentially involved in Ang II-mediated hypertrophy, is dose dependently reduced by RV. Consistent with these results, we show that RV attenuates phosphorylation of the p70 ribosomal protein S6 kinase (p70 S6K ), a kinase downstream of the ERK 1/2 as well as the Akt pathway, that is implicated in Ang II-induced protein synthesis. Upstream of Akt/PKB RV seems to mediate its antihypertrophic effect by inhibiting phosphorylation of the phosphatidylinositol 3-kinase (PI 3 K) rather than by activating phosphatases. In summary, we demonstrate for the first time that RV inhibits Ang II-induced VSMC hypertrophy, possibly by interfering mainly with the PI 3 K/Akt and p70 S6K but also with the ERK

Resveratrol inhibits type II phosphatidylinositol 4-kinase: A key component in pathways of phosphoinositide turn over

“…Resveratrol has been implicated in PtdIns 3-kinase mediated signaling cascades [35,36]. The concentrations required for inhibition of PtdIns 3-kinase is significantly on the higher side compared to our studies.…”

Resveratrol attenuates angiotensin II-induced interleukin-6 expression and perivascular fibrosis

“…16 Resveratrol is reported to suppress Ang II-induced Akt activation and extracellular signal-regulated protein kinase to a lesser extent. 17 However, the effect of resveratrol on Ang II-induced cytokine production remains to be determined. We, therefore, examined in this study whether resveratrol inhibits the Ang II-induced IL-6 expression in VSMCs.…”

A metabolic perturbation by U0126 identifies a role for glutamine in resveratrol-induced cell death

“…Resveratrol has been shown to inhibit glucose uptake 62,63 leading to loss of p70S6K phosphorylation. 64,65 As glucose levels in the cell decline, glycosylation is inhibited and plasma membrane levels of growth factor receptors and transporters are reduced, 66 including the glutamine importer ASCT2. Glutamine importers are upregulated in a number of cancer cells lines 67,68 possibly through autocrine growth factor signaling, 69 leading to a glutamine "addiction" phenotype.…”