Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 8, Pages 5963-5972Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.392050
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [22590245]
- National Project of Knowledge Cluster Initiative of Second Stage, Sapporo Biocluster Bio-S
- Regional R&D Proposal-based Program from the Northern Advancement Center for Science and Technology of Hokkaido
- Tubasa Foundation
- Hokkaido Heart Association grant for research
- Fukuda Foundation for Medical Technology
- Akiyama Life Science Foundation
- Grants-in-Aid for Scientific Research [23591086, 23591085, 22590245] Funding Source: KAKEN
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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 alpha(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.
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