Abstract 11173: Resveratrol Displays Cardioprotection in Postinfarction Remodeling Through Autophagic Activation Associated With Ampk but not Sirt1 Pathway
Resveratrol is a popular natural polyphenolic compound and recently reported to have strong autophagy-accelerating property. We investigated the possible therapeutic effect of resveratrol on established myocardial infarction and the underlying molecular mechanisms in present study. Large myocardial infarction was induced in mice by the left coronary artery ligation. Four weeks postinfarction, the surviving mice were assigned to five following groups: vehicle (n=16), low-dose resveratrol (5 mg/kg/day, n=16), high-dose resveratrol (50 mg/kg/day, n=16), chloroquine (an autophagy inhibitor, 10 mg/kg/day, n=16) or high-dose resveratrol plus chloroquine (n=16). High-dose (but low-dose) resveratrol partially reversed left ventricular dilatation (reverse remodeling) and significantly ameliorated cardiac dysfunction compared with the vehicle. Autophagy was augmented in those hearts, as indicated by upregulation of myocardial microtubule-associated protein-1 light chain 3-II (LC3-II). In addition, electron microscopy revealed increased numbers of autophagic vacuoles. The activities of AMP-activated protein kinase (AMPK) and silent information regulator-1 (Sirt1) were enhanced in hearts treated with resveratrol, and the activities of mammalian target of rapamycin (mTOR) and p70 S6 kinase (a direct down-stream target of mTOR) were suppressed, whereas Akt activity and MnSOD levels were unchanged among the groups. Chloroquine brought about opposite results, including deterioration of cardiac dysfunction and remodeling. This was associated with a reduction in autophagic activity and inactivation of AMPK but was irrelevant to Sirt1 activity. In vitro, resveratrol augmented autophagy in neonatal cardiomyocytes accompanying AMPK activation and ATP production, while compound c (an AMPK inhibitor) offset these effects. In conclusion, resveratrol is a beneficial pharmacological tool that augments autophagy to bring about reverse remodeling in the postinfarction heart.
- © 2012 by American Heart Association, Inc.