Resveratrol Improves Cardiomyopathy in Dystrophin-deficient Mice through SIRT1 Protein-mediated Modulation of p300 Protein[S]

Cardiomyopathy is the main cause of death in Duchenne muscular dystrophy. Here, we show that oral administration of resveratrol, which leads to activation of an NAD+-dependent protein deacetylase SIRT1, suppresses cardiac hypertrophy and fibrosis and restores cardiac diastolic function in dystrophin-deficient mdx mice. The pro-hypertrophic co-activator p300 protein but not p300 mRNA was up-regulated in the mdx heart, and resveratrol administration down-regulated the p300 protein level. In cultured cardiomyocytes, cardiomyocyte hypertrophy induced by the α1-agonist phenylephrine was inhibited by the overexpression of SIRT1 as well as resveratrol, both of which down-regulated p300 protein levels but not p300 mRNA levels. In addition, activation of atrial natriuretic peptide promoter by p300 was inhibited by SIRT1. We found that SIRT1 induced p300 down-regulation via the ubiquitin-proteasome pathway by deacetylation of lysine residues for ubiquitination. These findings indicate the pathological significance of p300 up-regulation in the dystrophic heart and indicate that SIRT1 activation has therapeutic potential for dystrophic cardiomyopathy. Background: Dystrophin deficiency leads to life-threatening cardiomyopathy, whereas cardiac p300 promotes cardiac hypertrophy/failure. Results: The SIRT1 activator resveratrol inhibited p300 protein up-regulation and attenuated cardiomyopathy in dystrophin-deficient mice, and SIRT1-induced p300 down-regulation was mediated via its deacetylation and ubiquitination. Conclusion: SIRT1 activation ameliorates dystrophic cardiomyopathy by targeting p300. Significance: Negative regulation of p300 is a novel cardioprotective mechanism of SIRT1.