Abstract 186: Impaired Nucleocytoplasmic Shuttling and Activity of SIRT1 in Response to Ischemic Stress in the Senescent Heart
Background: Numerous investigators have observed a decreased ability of the senescent heart to tolerate ischemic stress in both animal models and humans. However, 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 hypothesize 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. The results indicate that SIRT1 is predominantly expressed in a sumoylated form at Lys 734 in the nuclei of cardiomyocytes. Moreover, protein levels of SIRT1 in the aged heart are significantly lower than those in young hearts (n=6 per group, p<0.05). Confocal fluorescence microscopy 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 see in young hearts (p<0.01). Moreover, 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 peroxisome proliferator-activated receptor γ coactivator 1-α (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 and activity of cardiac SIRT1. Modulation of SIRT1's action in the senescent heart can be a strategy for limiting cardiac ischemic injury in older individuals.
- © 2010 by American Heart Association, Inc.