Abstract 15808: SIRT6 Deacetylase Blocks Cardiac Hypertrophic Response by Blocking Expression of IGF/Akt Signaling Related Genes at the Level of Chromatin
Physical exercise and calorie restriction (CR) have been shown to exert beneficial effects to patient with heart failure. A great body of evidence also suggests that these interventions increase activity of sirtuins (SIRT1-SIRT7), thus suggesting that beneficial effects of exercise and CR to a failing heart could be mediated by activation of a sirtuin analogue. This study was undertaken to test the effect of SIRT6, a chromatin bound H3K9 deacetylase which is activated by exercise and CR, on the development of cardiac hypertrophy. By analyzing SIRT6 levels in human non-failing (n=6) and failing (n=24) hearts, we found that they were significantly reduced in failing hearts. Similarly, SIRT6 levels were also reduced in animal models of cardiac hypertrophy induced by trans-aortic constriction (TAC) or isoproterenol infusion, thus suggesting that SIRT6-deficiency could be contributing to evolution of pathologic cardiac hypertrophy. To directly test the effect of SIRT6 deficiency on development of hypertrophy, we deleted SIRT6 in the adult mouse heart (Sirt6-KO) by using tamoxifen inducible α-MHC-Cre system. Sirt6-KO mice spontaneously developed cardiac hypertrophy with significantly reduced contractile functions following 3 months of deletion. On the other hand, transgenic mice having cardiac specific overexpression (3-5 fold) of SIRT6 (SIRT6-Tg) were resistant to develop TAC-mediated cardiac hypertrophy. By using microarray and biochemical analyses, we found a substantial increase in protein and mRNA levels of IGF/Akt signaling-related genes, including IGF1R, InsR, Akt, Foxo1, GSK3, and IGF2 and transcription and translation factors acting downstream of IGF signaling, including Myc, β-catenin, eIF4E, S6P and p70S6K in SIRT6-KO hearts. Conversely, SIRT6-Tg hearts showed attenuated expression of these IGF/Akt signaling genes. The results obtained from ChIP assays indicated that SIRT6 binds to and regulates promoters of IGF signaling genes by deacetylating H3K9. These data thus indicate that SIRT6 negatively regulates development of cardiac hypertrophy by controlling expression of IGF/Akt signaling related genes at the level chromatin.
- © 2012 by American Heart Association, Inc.