Abstract 8274: Resveratrol Brings About Reverse Remodeling In The Heart With A Large Old Myocardial Infarction Through Autophagy Activating amp Kinase Pathway
We previously reported that autophagy is activated during postmyocardial infarction and compensates for the lack of energy in cardiomyocytes by digesting and recycling own constituents. Resveratrol is a popular natural polyphenolic compound, abundantly contained in the skin of grapes and red wine, and is recently reported to have not only an anti-oxidant property but also autophagy-accelerating action. We here investigated the effect of resveratrol on established heart failure due to a large old myocardial infarction. Myocardial infarction was induced in mice by the left coronary artery ligation. Four weeks post-infarction, the surviving mice were assigned to four groups: control (saline, n=15); resveratrol (50 mg/kg/day, n=15); chroloquine (an autophagy inhibitor, 10 mg/kg/day, n=15); and combination (resveratrol, 50 mg/kg/day plus chroloquine, 10 mg/kg/day, n=15). The agents were administered for 2 weeks using osmotic mini pump. Resveratrol significantly attenuated and partially reversed left ventricular dilatation (reverse remodeling) and improved function: left ventricular end-diastolic diameter, 4.1±0.2 mm vs. 4.9±0.3 mm in controls; and ejection fraction, 46.9±3.3 % vs. 35.8±3.3 % in controls (p<0.05), accompanying reduction of ventricular expression of atrial natriuretic peptide. In those hearts, autophagic findings were augmented as shown by upregulation of microtubule-associated protein-1 light chain 3-II (LC3-II) and by electron microscopic findings of autophagic vacuoles. The activation of AMP-activated protein kinase was enhanced in the hearts treated with resveratrol while the activation of mammalian target of rapamycin complex 1 (mTORC1) and p70S6 kinase (a direct down-stream target of mTORC1) was suppressed compared to vehicle. Chroloquine brought about an opposite result, including aggravation of cardiac dysfunction and remodeling progression, where autophagic activity was diminished. A combined treatment with resveratrol and chroloquine offset each effect on the postinfarction heart. Any treatment did not affect apoptosis in the infarcted heart. The present findings suggest that resveratrol is new pharmacological strategy -i.e., manipulation of autophagy, against postinfarction cardiac remodeling.
- © 2011 by American Heart Association, Inc.