Pharmacological activation of SIRT1 protects against cardiac ischemic injury in the senescent heart
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Aging is associated with a reduced tolerance to myocardial ischemia/reperfusion (I/R) injury. SIRT1, a putative anti-aging protein, attenuates the age-dependent decline in cardiac function and protects against oxidative injury in the heart. Here we examined whether intervention utilizing SIRT1 can improve the tolerance of the aged heart to ischemic stress. Localization studies have established that cardiac SIRT1 is predominantly localized in the nucleus, and covalently conjugated with Sumo-1 protein. SIRT1 protein levels in the hearts of aged (24-26 months-old) C57BL/6 mice are significantly lower than those in young (2-6 months-old) hearts. In addition, nuclear SIRT1 activity in ischemic aged hearts is about 50% lower than that in ischemic young hearts, suggesting that aging impairs SIRT1 activation in response to ischemic stress. In addition, aged hearts fail to maintain SIRT1 protein nuclear localization. Tail vein injection of SRT1720, which is a specific SIRT1 activator, significantly enhanced the interaction between SIRT1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the nuclei of cardiomyocytes, and decreased nuclear acetyl-PGC-1α in the heart as well, indicating SRT1720 activates cardiac SIRT1 in vivo. For HL-1 cardiomyocytes, SRT1720 administration demonstrated that SIRT1 activation is associated with SIRT1 protein sumoylation and migration from cytoplasm to nucleus. Moreover, after 20 minutes of left anterior descending coronary artery ligation followed by 4 hours of reperfusion, myocardial infarct size in aged and Sirt1+/− hearts are markedly higher than in young and Sirt1+/+ hearts. However, pre-treatment with either resveratrol or SRT1720 dramatically reduced infarct size in aged and Sirt1+/− hearts. Similarly, both resveratrol and SRT1720 treatments enhanced cardiac contractility in the aged heart compared to vehicle after 20 minutes of global ischemia ex vivo. SRT1720 treatment significantly stimulated fatty acid metabolism in both young and aged hearts, while did not apparently influence glucose uptake as shown by ex vivo working heart model. Apoptosis was inhibited in SRT1720 pre-treated aged hearts during I/R, which could be correlated with SIRT1 cardioprotective function. Sumoylation inhibitor blocked the anti-apoptotic effect of SRT1720. The results suggest that increased susceptibility of the aged heart to I/R injury is largely attributed to impaired cardiac SIRT1 protein levels and activity, and pharmacological SIRT1 activation can restore cardioprotection in the aged heart during I/R. The present study is the first to report that cardiac SIRT1 is predominantly expressed in the nuclei in a sumoylated form. The aged heart possesses lower SIRT1 protein levels and impaired SIRT1 activation during I/R, so that SIRT1 could be a promising therapeutic interventional target for elderly ischemic heart disease patients.