Abstract
The sirtuin SIRT6 is a chromatin bound enzyme which is implicated in extending lifespan of animals. However, the mechanism of longevity effects of SIRT6 is not known. This study was undertaken to test the effect of SIRT6 on the development of cardiac hypertrophy and heart failure. SIRT6 levels were significantly reduced in mouse aging hearts, and in hearts subjected to develop cardiac hypertrophy by trans‐aortic constriction or agonist infusion. To directly test the effect of SIRT6 deficiency on the development of cardiac hypertrophy, we deleted SIRT6 in the adult mouse heart (SIRT6KO). SIRT6KO mice spontaneously developed cardiac hypertrophy with sever fibrosis and degenerative changes in mitochondria. These hearts also expressed higher levels of aging associated cytoskeletal proteins, fibrotic markers and apoptotic genes. SIRT6KO hearts also had increased expression of several IGF‐Akt signaling related genes. Conversely, transgenic mice having cardiac specific overexpression of SIRT6 were resistant to develop cardiac hypertrophy, and these hearts had attenuated expression of aging associated proteins and IGF‐Akt signaling related genes. ChIP analyses reveled that SIRT6 regulates IGF‐Akt signaling genes by deacetylating H3K9. These data thus indicated that SIRT6 protects the heart from developing hypertrophy by blocking expression of IGF‐Akt signaling related genes at the level chromatin.
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