Abstract 11344: Impaired SIRT1 Nucleocytoplasmic Shuttling in the Senescent Heart during Ischemic Stress
Background- A decreased ability to tolerate ischemic stress with aging is observed in both animal models and humans. A ‘longevity’ gene, sirtuin 1 (SIRT1), has been reported to attenuate the age-dependent induction of left ventricular dysfunction. We hypothesize that SIRT1 is involved in intolerance of the aged heart to ischemic stress.
Methods and Results- Male C57BL/6 young (4-6 months) and aged (24-26 months) mice were used to determine SIRT1’s role in myocardial ischemia/reperfusion (I/R) tolerance. We for the first time found that SIRT1 is predominantly expressed in a sumoylated form in cardiomyocyte nuclei, and that overexpression of desumoylase, sentrin-specific protease 2(SENP2), can reduce nuclear sumoylated SIRT1 levels. Interestingly, SIRT1 protein levels in aged hearts are lower than those seen in young hearts (p<0.05). Immunoblotting and confocal fluorescence data demonstrated that I/R triggers desumoylation and translocation of nuclear SIRT1 into the cytoplasm in aged but not in young hearts. In addition, nuclear SIRT1 activity in ischemic young hearts was 3.2-fold higher than that seen in ischemic aged hearts (p<0.05), suggesting that aging causes impaired nucleocytoplasmic shuttling and activation of SIRT1 in response to ischemic stress. Wild type (WT) and Sirt1+/- knockout mice (all C57BL/6 background) were subjected to 30 min ischemia via left anterior descending (LAD) coronary artery occlusion followed by 4 hours reperfusion, the infarct size in aged and Sirt1+/- knockout hearts was markedly higher than that observed in young and Sirt1+/+ WT littermate hearts, respectively. Furthermore, the SIRT1 agonist, SRT1720, significantly reduced infarct size in both aged and Sirt1+/- hearts via activation of cardiac SIRT1.
Conclusions - Impaired cardiac SIRT1 activity plays a key role in the observed increase in susceptibility of the aged heart to ischemia/reperfusion (I/R) injury. Pharmacological SIRT1 activation can restore this aging-related loss of cardioprotection against I/R injury.
- © 2012 by American Heart Association, Inc.