Cardioprotection by resveratrol PDF Print E-mail

Cardiovasc Res. 2009 Dec 3. [Epub ahead of print]

Cardioprotection by resveratrol: A novel mechanism via autophagy involving the mTORC2 pathway.

Gurusamy N, Lekli I, Mukherjee S, Ray D, Ahsan MK, Gherghiceanu M, Popescu LM, Das DK. Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT, USA.

AIMS: Based on our previous reports that cardioprotection induced by ischemic preconditioning induces autophagy and that resveratrol, a polyphenolic antioxidant present in grapes and red wine induces preconditioning-like effects, we sought to determine if resveratrol could induce autophagy. Methods and Results Resveratrol at lower doses (0.1 and 1 microM in H9c2 cardiac myoblast cells, and 2.5 mg/kg/day in rats) induced cardiac autophagy shown by enhanced formation of autophagosomes and its component LC3-II after hypoxia-reoxygenation or ischemia-reperfusion. The autophagy was attenuated with the higher dose of resveratrol. The induction of autophagy was correlated with enhanced cell survival and decreased apoptosis. Treatment with rapamycin (100 nM), a known inducer of autophagy did not further increase autophagy compared to resveratrol alone. Autophagic inhibitors, Wortmannin (2 microM) and 3-methyladenine (10 mM), significantly attenuated the resveratrol-induced autophagy and induced cell death. The activation of mammalian target of rapamycin (mTOR) was differentially regulated by low-dose resveratrol; i.e. the phosphorylation of mTOR at serine 2448 was inhibited while the phosphorylation of mTOR at serine 2481 was increased, which was attenuated with a higher dose of resveratrol. Although resveratrol attenuated the activation of mTOR complex1, low-dose resveratrol significantly induced the expression of Rictor, a component of mTOR complex 2, and activated its downstream survival kinase Akt (Ser473). Resveratrol-induced Rictor was found to bind with mTOR. Furthermore, treatment with Rictor siRNA attenuated the resveratrol-induced autophagy. CONCLUSIONS: Our results indicate that at lower dose, resveratrol-mediated cell survival is, in part, mediated through the induction of autophagy involving mTOR-Rictor survival pathway.

PMID: 19959541 [PubMed - as supplied by publisher]




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