title: Resveratrol improves cardiomyopathy in dystrophin-deficient mice through SIRT1 protein-mediated modulation of p300 protein.
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 α(1)-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.
authors.affiliation: Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuno
authors.forename: Yusuke S
authors.initials: YS
authors.lastname: Hori
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Hosoda
authors.forename: Masaya
authors.initials: M
authors.lastname: Tanno
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Miura
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimamoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Horio
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism; D009202:Cardiomyopathies / Q000188:drug therapy*; D015536:Down-Regulation; D016189:Dystrophin / Q000235:genetics*; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D004452:Echocardiography / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010656:Phenylephrine / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics*; D013267:Stilbenes / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016189:Dystrophin; D013267:Stilbenes; D025801:Ubiquitin; D010656:Phenylephrine; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D046988:Proteasome Endopeptidase Complex; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol