Abstract 13016: SIRT6 Plays an Essential Role in Regulating IGF Signaling and Aging Associated Cardiac Failure
Aging is the major risk factor for heart failure. However, the molecular mechanisms that link aging with cardiac failure are not yet understood. Previous studies have demonstrated dysregulation of insulin-like growth factor (IGF) signaling in mammalian aging and in aging associated diseases like diabetes, obesity and heart failure. In this study, we determined an essential role of SIRT6, a chromatin associated NAD-dependent nuclear deacetylase, in regulating IGF signaling and aging associated cardiac failure. SIRT6 levels were dramatically reduced in human end-stage failing hearts and in the mouse model of pressure overload hypertrophy. SIRT6 null mice (Sirt6KO) unveiled premature aging with cardiac failure accompanied by concentric hypertrophy, increased cell size, apoptosis, fibrosis, fetal genes expression and degenerative changes in mitochondria. Similar to Sirt6KO, Sirt6(+/-) mice spontaneously developed cardiac failure at 6 months of age, suggesting that 50% reduction of SIRT6 is sufficient to induce cardiac failure. Analysis of Sirt6KO hearts revealed hyperactivation of IGF signaling and its target transcription factors NFAT, Myc and β-catenin and translation factors elf4E, S6P and p70S6K. SIRT6 deficiency resulted in uncontrolled transcription of several IGF signaling components including Igf1r, Igf2r, Igf2, Irs2, Mapk3, Akt3 and mTOR as revealed by comparative microarray and real-time PCR analysis. Chromatin immunoprecipitation experiments indicated that SIRT6 directly binds and represses the promoter of IGF signaling genes by interacting with the transcription factor c-Jun. Lack of SIRT6 enhanced the promoter binding and transcriptional activity of c-Jun, which resulted in over-activation of IGF signaling and thereby developing cardiac aging and failure. In contrast, forced expression of SIRT6 in neonatal cardiomyocytes blunted the agonist-induced hypertrophy. Transgenic mice with cardiac-specific over-expression of SIRT6 exhibited reduced activation of IGF signaling and were protected against isoproternol-induced cardiac hypertrophy and failure. These findings identify a novel molecular link between aging and heart failure and suggest a new strategy for treating cardiac failure through activation of SIRT6.
- © 2011 by American Heart Association, Inc.