Abstract 12266: Long-Term Treatment with the SIRT1 Activator Resveratrol Ameliorates Cardiomyopathy in Dystrophin-Deficient Mice
Background: Loss of cardiac dystrophin eventually leads to cardiac dysfunction and heart failure, which is a main cause of death in patients with Duchenne muscular dystrophy (DMD). However, there is still no effective pharmacological therapy. Here, we examined the effect of resveratrol, an activator of the longevity factor SIRT1, on cardiomyopathy in dystrophin-deficient mice (mdx), a model of DMD.
Methods and Results: Mdx were left untreated or received resveratrol (400 mg/kg/day orally) for 32 weeks starting at 9 weeks of age. Age-matched C57BL10 served as controls. Mice were examined by echocardiography at 40 weeks of age and sacrificed. Compared with C57BL10, mdx showed significant cardiac hypertrophy as evidenced by higher heart-to-body weight (HW/BW) ratio (4.1±0.6 vs. 5.4±0.8 mg/g), increased diastolic ventricular thickness (0.72±0.02 vs. 0.82±0.03 mm), larger cardiomyocyte cross-sectional area (1.7 fold), and induction of atrial natriuretic peptide mRNA expression (4.3 fold). Resveratrol treatment significantly attenuated cardiac hypertrophy (HW/BW: 4.2±0.1) in mdx. Left ventricular (LV) dimension and LV ejection fraction were similar among the three study groups, but diastolic posterior wall movement, an index of LV diastolic function, was improved by resveratrol in mdx (20.8±0.7 vs. 26.2±1.3 mm/sec, p<0.05). Tissue area stained for fibronectin and tissue level of collagen mRNA, two indices of fibrosis, in mdx were reduced to 48% and 57% of untreated controls, respectively, by resveratrol. Myocardial mRNA level of the fibrogenic cytokine TGFβ1, extent of phosphorylation of extracellular signal-regulated kinase 1/2, mediators of cardiac hypertrophy and fibrosis, in mdx hearts were not reduced by resveratrol. However, resveratrol suppressed the upregulation of protein level of the transcription co-activator p300, a pro-hypertrophic and -fibrotic protein acetylase, in the mdx myocardium. In C2C12 myoblasts, resveratrol decreased p300 protein, and this effect was blocked by SIRT1 knockdown.
Conclusion: Resveratrol attenuates ventricular fibrosis and improves diastolic LV function in mdx presumably by p300 downregulation via SIRT1 activation. SIRT1 activation may be a novel strategy in treatment of cardiomyopathy in DMD.
- © 2011 by American Heart Association, Inc.