Abstract 100: Mechanisms That Mediate the Cardioprotective Activities of Resveratrol in Pressure Overload-Induced Heart Failure

Abstract

We previously demonstrated that the potent antioxidant, resveratrol, significantly attenuates the adverse cardiac remodeling and dysfunction in pressure overload heart failure induced by transverse aortic constriction (TAC) in C57/BL6 mice. The purpose of this study was to identify the mechanisms that mediate the cardioprotective activities of resveratrol in this setting. Male C57BL6 mice (26-28 g) were subjected to either sham or TAC surgery. One group of TAC mice was given daily resveratrol treatment (oral gavage, 100 mg/kg/body weight for 28 days starting on day 2 after surgery. At the end of the protocol (28 days), the hearts were removed for analysis of markers of oxidative stress, inflammation, and apoptosis. Immunohistological staining for left ventricular (LV) 4-hydroxy-2-nonenal, a marker of lipid peroxidation was significantly elevated in the TAC mice (18.4±3.0 IOD/μm 2 ) compared to sham mice (3.4±1.0). Resveratrol treatment significantly attenuated this increase (14.4±2.0). In contrast, LV content of the antioxidant glutathione was significantly decreased in the TAC mice (5.3±0.2 nM/mg protein) compared to the sham mice (8.5±0.2). Resveratrol treatment significantly increased glutathione (7.6±0.3) to near sham levels. Likewise, LV activity of sodium oxide dismutase 2 was markedly reduced in TAC mice (7.3±0.9 U/mg protein) compared to sham mice (10.7±1.3) and was significantly increased by resveratrol treatment (7.6±0.3). LV macrophage and mast cell infiltration was markedly increased in the TAC mice (14.8±0.1 and 12.6±0.0 %) compared to sham mice (1.7±0.1 and 2.6±0.1). This increase was significantly attenuated by resveratrol administration (10.4±0.1 and 8.0±0.1). Apoptotic cell death, as determined by the TUNEL assay, was also increased in the TAC mice (0.13±0.01 % cells) compared to sham mice (0.01±0.01). This increase was significantly attenuated in the resveratrol treated group (0.06±0.01). A similar pattern was observed when activated LV caspase-3, a second marker of apoptosis, was measured. In conclusion, these data indicate that the cardioprotective effects of resveratrol in pressure overload-induced heart failure are mediated through the inhibition of oxidative stress, inflammation, and apoptotic cell death.