Abstract 1781: Activation of a Protein Deacetylase, SIRT1, by Resveratrol Suppresses Progression of Heart Failure and Improves Survival by Up-Regulation of Mn-SOD

Abstract

[Purpose] SIRT1, a protein deacetylase, induces cellular resistance against oxidatnt stress by deacetylating forkhead transcription factors and p53. However, the physiological significance of the protection and the role of endogenous free radical scavengers have not been clarified. Here, we examined involvement of Mn-SOD in the SIRT1-mediated protection and possible benefit of a SIRT1 activator, resveratrol (RSV), for suppressing progression of heart failure. [Methods and Results] First, capacity of SIRT1 to prevent oxidant-induced apoptosis and its mechanism were examined in cardiomyocytes. Apoptosis induced by antimycin A (AA, 30 μM), an oxidant stressor, was suppressed by transfection with wild-type SIRT1 (WT) (4.4±0.7%) compared with the control (40.4±5.5%), while deacetylase-inactive SIRT1 (H355Y) was not protective (38.0±8.1%). WT, but not H355Y, increased Mn-SOD by 3.7 fold, and knockdown of Mn-SOD by siRNA abolished both up-regulation of Mn-SOD and protection against AA. RSV (100 μM) significantly reduced acetyl-histone H3 level and mimicked the effect of WT on AA-induced apoptosis (26.5±4.8% vs. 11.5±1.1%). These effects were attenuated by siRNA-mediated knockdown of SIRT1, indicating that SIRT1 is required for the protection. Second, the effect of SIRT1 activation by RSV on heart failure was examined in TO-2 cardiomyopathic hamsters. Treatment with RSV (4 g/kg in chow) was commenced at the age of 6 weeks. Echocardiography was performed at 25 weeks, and determination of mRNA levels and immunohistochemistry were performed at 35 weeks. Compared with those in controls, LVEF was significantly better preserved (34.3±2.2% vs. 27.9±1.6%, p=0.02), Mn-SOD protein was increased by 32% (p=0.04), BNP mRNA level was reduced by 31% (p<0.01) and interstitial fibrosis detected by fibronectin staining was decreased by 53% (p=0.02). Furthermore, Kaplan-Meier analysis revealed that RSV significantly improved the survival of TO-2 hamsters from 7% to 27% during a 51-week follow-up period (n=29, Hazard ratio = 0.417, χ2 = 4.83, p=0.028 vs. control). [Conclusion] Progression of heart failure and death can be suppressed by activation of SIRT1 by the use of RSV, this being attributable to suppression of cardiomyocyte apoptosis by up-regulation of Mn-SOD.