Resveratrol Improves Cardiomyopathy in Dystrophin-deficient Mice through SIRT1 Protein-mediated Modulation of p300 Protein |
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Authors: | Atsushi Kuno Yusuke S. Hori Ryusuke Hosoda Masaya Tanno Tetsuji Miura Kazuaki Shimamoto Yoshiyuki Horio |
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Affiliation: | From the ‡Department of Pharmacology and ;§Second Department of Internal Medicine, Sapporo Medical University School of Medicine and ;¶Sapporo Medical University, Sapporo 060-8556, Japan |
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Abstract: | 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. |
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Keywords: | Dystrophin Heart p300 Sirt1 Ubiquitination Cardiomyopathy Protein Deacetylation |
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