Silent information regulator 1 protects the heart from ischemia/reperfusion

Chiao Po Hsu, Peiyong Zhai, Takanobu Yamamoto, Yasuhiro Maejima, Shouji Matsushima, Nirmala Hariharan, Dan Shao, Hiromitsu Takagi, Shinichi Oka, Junichi Sadoshima

Research output: Contribution to journalArticle

330 Scopus citations

Abstract

Background-: Silent information regulator 1 (Sirt1), a class III histone deacetylase, retards aging and protects the heart from oxidative stress. We here examined whether Sirt1 is protective against myocardial ischemia/reperfusion (I/R). Methods and results-: Protein and mRNA expression of Sirt1 is significantly reduced by I/R. Cardiac-specific Sirt1 mice exhibited a significant increase (44±5% versus 15±5%; P=0.01) in the size of myocardial infarction/area at risk. In transgenic mice with cardiac-specific overexpression of Sirt1, both myocardial infarction/area at risk (15±4% versus 36±8%; P=0.004) and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive nuclei (4±3% versus 10±1%; P<0.003) were significantly reduced compared with nontransgenic mice. In Langendorff-perfused hearts, the functional recovery during reperfusion was significantly greater in transgenic mice with cardiac-specific overexpression of Sirt1 than in nontransgenic mice. Sirt1 positively regulates expression of prosurvival molecules, including manganese superoxide dismutase, thioredoxin-1, and Bcl-xL, whereas it negatively regulates the proapoptotic molecules Bax and cleaved caspase-3. The level of oxidative stress after I/R, as evaluated by anti-8-hydroxydeoxyguanosine staining, was negatively regulated by Sirt1. Sirt1 stimulates the transcriptional activity of FoxO1, which in turn plays an essential role in mediating Sirt1-induced upregulation of manganese superoxide dismutase and suppression of oxidative stress in cardiac myocytes. Sirt1 plays an important role in mediating I/R-induced increases in the nuclear localization of FoxO1 in vivo. Conclusions-: These results suggest that Sirt1 protects the heart from I/R injury through upregulation of antioxidants and downregulation of proapoptotic molecules through activation of FoxO and decreases in oxidative stress.

Original languageEnglish (US)
Pages (from-to)2170-2182
Number of pages13
JournalCirculation
Volume122
Issue number21
DOIs
StatePublished - Nov 23 2010
Externally publishedYes

Keywords

  • cardioprotection
  • ischemia
  • oxidative stress
  • reperfusion injury

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Hsu, C. P., Zhai, P., Yamamoto, T., Maejima, Y., Matsushima, S., Hariharan, N., Shao, D., Takagi, H., Oka, S., & Sadoshima, J. (2010). Silent information regulator 1 protects the heart from ischemia/reperfusion. Circulation, 122(21), 2170-2182. https://doi.org/10.1161/CIRCULATIONAHA.110.958033