Abstract 1821: The Longevity Factor Sirt1 Protects Heart from Ischemia/Reperfusion Stress
Sirt1, a class III histone deacetylase, extends the lifespan of many organisms. Longevity mechanisms confer stress resistance to organisms, and accumulation of stress resistance leads to lifespan extension. We have shown previously that Sirt1 is upregulated by stress up to 10 fold in the heart, and heart specific overexpression (7.5 fold in line #40) of Sirt1 in mice suppresses markers of aging, and induces resistance to oxidative stress in the heart. However, the same 7.5 fold overexpression of Sirt1 rather exacerbated heart failure in response to pressure overload, suggesting that Sirt1 may confer stress resistance to the heart against only particular types of stress. We here examined whether Sirt1 is protective against ischemia/reperfusion (I/R) injury in the heart. Cardiac specific Sirt1 transgenic mice (Tg-Sirt1) from line #40 were subjected to 45 min of ischemia followed by 24 h of reperfusion. In non-transgenic (NTg) mice, protein expression of Sirt1 was downregulated after I/R (64.9 ± 2.5% of sham, p < 0.05). Heart homogenates prepared from Tg-Sirt1 mice exhibited lower levels of acetylated proteins, including p53, with or without I/R, as determined by anti-acetylated lysine antibody, suggesting that the deacetylase activity is elevated in Tg-Sirt1. After I/R, the size of myocardial infarction (MI)/area at risk (AAR), as determined by TTC staining, was significantly smaller in Tg-Sirt1 than in NTg (14.9 ± 4.4% vs. 36.2 ± 8.3%, p = 0.001). There was no significant difference in the size of AAR between Tg-Sirt1 and NTg. The number of TUNEL positive nuclei in the ischemic area was significantly smaller in Tg-Sirt1 than in NTg (9.1 ± 12.0 % vs. 36.0 ± 3.6%, p< 0.05). In Tg-Sirt1 hearts, the amount of Mn-superoxide dismutase and thioredoxin1, major antioxidants, are significantly increased (9.3 ± 1.5 fold, p < 0.001, 1.9 ± 0.4 fold, p < 0.05), while Bax (0.2 ± 0.1 fold, p = 0.01) and cleaved caspase 3 (0.3 ± 0.1 fold, p < 0.05), proapoptotic molecules, are significantly decreased. These results suggest that upregulation of Sirt1 protects the heart from I/R injury. Sirt1 upregulates anti-oxidant whereas it downregulates proapoptotic molecules under I/R. In conclusion, cardioprotective effects of Sirt1 are stimulus-specific and Sirt1 is protective against I/R.