Inhibition of protein kinase C by resveratrol

AbstractEvidence is emerging that resveratrol (RV), a polyphenolic phytoaxelin present in dietary sources including red wine, may protect against atherosclerosis and cardiovascular disease by enhancing the integrity of the endothelium. In this study, the possibility that such beneficial effects of RV may arise from a modulation of protein kinase C (PKC)-mediated signaling was investigated by determining the effects of RV on the in vitro activities of PKC isozymes. It was found that the Ca2+-dependent activities of membrane-associated PKCα induced by either phorbol ester or diacylglycerol were potently inhibited by RV, each with an IC50 of ∼2 μM. The inhibitory effect of RV was also observed for conventional PKCβI, whereas the activities of novel PKCε and atypical PKCζ were each unaffected. The inhibition of PKCα activity was found to be competitive with respect to phorbol ester concentration but noncompetitive with respect to Ca2+ and phosphatidylserine concentrations, suggesting that the RV may compete for phorbol ester-binding to the C1 domains. Supporting this, it was found that RV bound to a fusion peptide containing the C1A and C1B domains of PKCα. Similar to the effects of diacylglycerol and phorbol ester, the interaction of RV with the C1 domains induced the association of PKCα with membrane lipid vesicles, although this did not result in activation. Overall, the results suggest that the inhibitory effect of RV on PKC activity, and therefore on the associated signaling networks, may, in part, underlie the mechanism(s) by which this agent exerts its beneficial effects on endothelial and cardiovascular function. Furthermore, the effects of RV on these signaling networks are predicted to differ according to the cellular localization and the regulating PKC isozyme