Abstract 10153: SIRT1 Activation Restores Cardioprotection in the Aged Heart Against Ischemia/Reperfusion Injury
Background: Aging is associated with a reduced tolerance to myocardial ischemia/reperfusion (I/R) injury. SIRT1, a putative anti-aging protein, is thought to be a potential interventional target for age-related ischemic heart disease due to its ability to attenuate the age-dependent decline in cardiac function. We hypothesized that SIRT1 is involved in the intolerance of the aged heart to ischemic stress.
Methods and Results: 4-6 months-old (young) and 24-26 months-old (aged) male C57BL/6 mice, 4-6 months-old male Sirt1+/- heterozygous knockout and Sirt1+/+ wild type littermates mice were used. The results show that SIRT1 is predominantly localized in the nuclei of cardiomyocytes, and SIRT1 protein levels in the aged hearts are significantly lower than those in young hearts; a similar discrepancy was also found between Sirt1+/- and Sirt1+/+ hearts (n=4-6, p<0.05). In addition, nuclear SIRT1 activity in ischemic aged hearts is 3.2-fold lower than that in ischemic young hearts (p<0.01), suggesting that aging impairs SIRT1 activation in response to ischemic stress. Tail vein injection of SRT1720 (0.02 μ g/g), a SIRT1 activator, significantly enhanced the interaction between SIRT1 and its downstream target PGC-1α in the nuclei of cardiomyocytes, and decreased acetylation of cardiac PGC-1α (p<0.01), indicating that SRT1720 can activate cardiac SIRT1 in vivo. Moreover, after 20 min of LAD coronary ligation followed by 4 hrs of reperfusion, myocardial infarction size in aged and Sirt1+/- hearts is markedly higher than in young and Sirt1+/+ hearts (45% and 31%, respectively, all p<0.01). However, pre-treatment with SRT1720 (0.02 μ g/g i.v.) 30 min before ischemia dramatically reduced infarct size in aged and Sirt1+/- hearts to 8% and 7%, respectively (all p<0.01). Additionally, compared to vehicle, SRT1720 treatment can significantly improve the post-ischemic recovery of aged heart (n=4-6, p<0.05 vs. vehicle).
Conclusions: Increased susceptibility of the aged heart to I/R injury is largely attributed to impaired cardiac SIRT1 activity, and pharmacological SIRT1 activation can restore tolernace of aged heart to ischemic insults. Therefore, modulating SIRT1 activity may be a beneficial therapeutic strategy for the elderly with acute coronary syndromes.
- © 2011 by American Heart Association, Inc.