Abstract 3603: SIRT1, a Stress-responsive Deacetylase is Required for Development of Compensatory Cardiac Hypertrophy
SIRT1, a NAD-dependent histone deacetylase is involved in regulation of various physiological functions. In variety of cell types SIRT1 levels are elevated during stress and that increases stress-tolerance of cells. SIRT1 levels are also elevated during cardiac hypertophy, induced either by chronic infusion of agonists (angiotensin or isoproterenol) or by trans-aortic constriction (TAC)-mediated pressure overload. However, the role of SIRT1 in development of cardiac hypertrophy is not yet understood. We hypothesized that elevated levels of SIRT1 regulate the development of compensatory cardiac hypertrophy. To test this hypothesis mice were fed a resveratrol (an SIRT1 activator) (0.067%) rich diet for 3 months and then they were subjected to TAC for 12 weeks. We found that mice fed with resveratrol diet developed significant amount of cardiac hypertrophy, as measured by increased HW/TL ratio (80%) and cross sectional area of myocytes, than the controls; but interestingly, they exhibited no markers of pathologic hypertrophy, such as cardiac fibrosis and induction of ANF or β-MHC, suggesting that SIRT1 might be involved in development of compensatory cardiac hypertrophy. To confirm these findings we did experiments with SIRT1 deficient (SIRT1-KO) mice of 4 weeks of age, which had smaller hearts than wild type controls. When SIRT1-KO mice were treated with hypertrophy agonists, they failed to develop cardiac hypertrophy; instead, they exhibited severe cardiomyocyte death and fibrosis. SIRT1 is known to induce IGF-1R signaling, which has been implicated in development of compensatory hypertrophy, we therefore, examined the activation of IGF-1R (phosphorylation) in SIRT3-KO mice, before and after treatments with agonists. Results showed that while IGF-1Rs were highly activated in hearts of resveratrol-fed mice, they remained unchanged in SIRT1-KO mice treated with hypertrophy agonists. The down-stream targets of IGF-1R signaling are Akt1 and ERK1/2, which were also activated in resveratrol-fed mice, but not in SIRT1-KO mice treated with agonists. From these studies we conclude that during cardiac stress, elevated levels of SIRT1 contribute to development of compensatory hypertrophy in part by activation of IGF1R-Akt1-ERK1/2 signaling.