AIMS: On the basis of our previous reports that cardioprotection induced by 
ischaemic 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 ischaemia-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 with 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, whereas 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 complex 1, low-dose resveratrol significantly induced the expression of 
Rictor, a component of mTOR complex 2, and activated its downstream survival 
kinase Akt (Ser 473). Resveratrol-induced Rictor was found to bind with mTOR. 
Furthermore, treatment with Rictor siRNA attenuated the resveratrol-induced 
autophagy.
CONCLUSION: Our results indicate that at lower dose, resveratrol-mediated cell 
survival is, in part, mediated through the induction of autophagy involving the 
mTOR-Rictor survival pathway.