Silent information regulator 1 protects the heart from ischemia/reperfusion

CP Hsu, P Zhai, T Yamamoto, Y Maejima… - Circulation, 2010 - Am Heart Assoc
CP Hsu, P Zhai, T Yamamoto, Y Maejima, S Matsushima, N Hariharan, D Shao, H Takagi…
Circulation, 2010Am Heart Assoc
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 …
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.
Am Heart Assoc