Abstract 1466: SIRT1 Overexpression Modulates Cardiac Metabolic Genes Expression and Induces Dilated Cardiomyopathy
SIRT1, a mammalian homolog of yeast Sir2, is an NAD+-dependent protein deacetylase. SIRT1 regulates lifespan in model organisms, and is also important in glucose and fatty acid metabolism. To examine the role of SIRT1 in the heart, we created and characterized transgenic mice overexpressing SIRT1 in a cardiac-specific manner. We analyzed mice showing high (20-fold), moderate (7-fold), or low (3-fold) SIRT1 protein expression. Mice with low or moderate SIRT1 expression were viable, but mice with high expression of SIRT1 died of heart failure at 3– 4 months of age. Echocardiographic findings of mice with low or moderate transgene expression were normal, whereas cardiac dilatation and reduced systolic function were noted in mice with high SIRT1 expression. Left ventricular pressure (LVP) and max dp/dt of mice during dobutamine infusion with low or moderate SIRT1 expression were normal, and LVP and max dp/dt of mice with high SIRT1 expression were markedly decreased compared with those of wild type mice. Heart weight of mice with low or moderate SIRT1 expression was normal, and heart weight of mice with high SIRT1 expression was increased by 1.2 fold compared with wild type mice. Expressions of genes related to metabolic regulation in the myocardium were examined in mice with low, moderate, and high SIRT1 expression. Fatty acid utilization genes (MCAD, CPT-1b, CD36/FAT), mitochondrial genes (Cyt-c, IDH-3alpha, CoxVa), transcriptional regulator genes (ERRalpha, NRF-1), and a glycolytic gene (PK) were decreased in a manner that was dependent on transgene dosage. In conclusion, SIRT1 overexpression modulated cardiac metabolic gene expression and induced dilated cardiomyopathy.