Emerging roles of SIRT1 deacetylase in regulating cardiomyocyte survival and hypertrophy

Abstract

Calorie restriction is considered to be the best environmental intervention providing health benefits to mammals. The underlying mechanism of this intervention seems to be controlled by a group of NAD-dependent deacetylases, collectively called sirtuins. In mammals, there are seven sirtuin analogs, SIRT1-SIRT7. The founding member of this family, SIRT1, is shown to protect cardiomyocytes from apoptosis and age-dependent degeneration in a dose dependent manner-protecting cells at low doses but showing detrimental effects at high doses. Studies performed with overexpression or knockdown of SIRT1 indicated that, although it protects cells from oxidative stress and ischemia-reperfusion injury, it promotes hypertrophy of cardiomyocytes. Activation of endogenous SIRT1 by resveratrol also displayed pro-survival and pro-hypertrophic activity of SIRT1. In this article, we review recent findings documenting the role of SIRT1 in regulating cardiac myocyte growth and survival under stress, and the proposed mechanism behind its cardioprotective effects. We also briefly discuss two other sirtuin analogs which have been shown to have cardioprotective effects. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure".

Figure 1. Simplified scheme illustrating mechanism of cardio-protective effects of SIRT1

In the adult hearts SIRT1 localizes mostly in the cytoplasm [11]. During stress stimulation of cells, PI3K/Akt and JNK are activated, which promote nuclear importation of SIRT1, perhaps by phosphorylation [11, 13]. In the nucleus SIRT1 activates transcription of Foxo-dependent anti-oxidant genes, MnSOD and catalase, leading to reduced cellular ROS (reactive oxygen species) levels and thus protecting cells from oxidative stress-mediated damage [12, 17]. There is also evidence documenting that SIRT1 increases expression of α-MHC and SERCa2A, resulting in enhanced heart function [25, 52].