Abstract 10395: Impaired Nucleocytoplasmic Shuttling of SIRT1 in the Senescent Heart in Response to Ischemic Stress
Background- Numerous investigators observed a decreased ability of the senescent heart to tolerate ischemic stress in both animal models and humans. However, the mechanisms responsible for ischemic intolerance in the aged heart are incompletely understood. A ‘longevity’ gene, sirtuin 1 (SIRT1), has been reported to attenuate age-dependent induction of hypertrophy, apoptosis, and consequent left ventricular dysfunction. We hypothesized that SIRT1 may be a factor involved in intolerance of the aged heart to ischemic stress.
Methods and Results- Male C57BL/6 mice 4-6 months of age (young) and 24-26 months of age (old) were used for determining SIRT1’s role in myocardial ischemia. Results indicate that SIRT1 is predominantly expressed in a sumoylated form in the nuclei of cardiomyocytes. Moreover, the levels of nuclear sumoylated SIRT1 in the heart overexpressing a SUMO isopepdidase SENP2 are significantly lower than that of WT hearts (p<0.01). The protein levels of SIRT1 in the aged heart are lower than those in young hearts (n=4-6, p<0.05). Confocal fluorescence data demonstrated that ex vivo global ischemia triggered desumoylation and translocation of nuclear SIRT1 into the cytoplasm. Intriguingly, the ratio of nucleocytoplamic shuttling by ischemic stress in old hearts was 10-fold higher than that seen in young hearts (p<0.01). In addition, nuclear SIRT1 activity in ischemic aged hearts was 3.2-fold lower than that in ischemic young hearts (p<0.05). In contrast, cytoplasmic SIRT1 activity in ischemic aged hearts was 2.5-fold higher than that in ischemic young hearts (p<0.01), suggesting that aging causes impaired nucelocytoplasmic shuttling of SIRT1 in response to ischemia. Furthermore, immunoprecipitation with SIRT1 antibody indicated that aging decreases the cardioprotective interaction between nuclear SIRT1 and PGC-1α during ischemia, resulting in an augmented cytoplasmic SIRT1-p53 apoptosis cascade in response to ischemic stress.
Conclusions- Increased susceptibility of the aged heart to ischemic stress may, in part, be attributed to impaired nucleocytoplasmic shuttling of cardiac SIRT1. Modulation of SIRT1 action and activity in the senescent heart could be a strategy for limiting cardiac ischemic injury in older individuals.
- © 2011 by American Heart Association, Inc.