Roles of SIRT3 in heart failure: from bench to bedside

Abstract

Heart failure (HF) represents the most common endpoint of most cardiovascular diseases (CVDs) which are the leading causes of death around the world. Despite the advances in treating CVDs, the prevalence of HF continues to increase. It is believed that better results of prognosis are obtained from prevention rather than additional treatment for HF. Therefore, it is reasonable to prevent the development of CVDs or other complications to HF. Most types of HF are attributed to contractile dysfunction, cardiac hypertrophy or remodeling, and ischemic injuries. SIRT3 is a mitochondrial nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase whose substrates vary from metabolic biogenesis-associated proteins to stress-responsive proteins. In recent years, a number of studies have highlighted the cardio-protective role of SIRT3 and, as such, efforts have been made to induce over-expression or increased activity of this protein. In this review, we provide an overview of the roles of SIRT3 in cardiac hypertrophy induced by pressure overload or agonists and cardiomyocytes ischemic injuries. Moreover, we will introduce the application of SIRT3 agonists in the prevention of cardiac hypertrophy and ischemia reperfusion injury.

Nicotinamide Riboside—The Current State of Research and Therapeutic Uses

“…In addition, SIRT2 and SIRT6 have emerged as prominent cardioprotective SIRTs [ 72 , 73 ], as deficiency of SIRT2 intensified cardiac hypertrophy in aged mice and mice stressed with angiotensin II [ 73 ], while a loss of SIRT6 in mice resulted in the development of cardiac hypertrophy and HF [ 74 ]. The activity of mitochondrial SIRTs is implicated in cardiac remodeling and the development of HF, including SIRT3 which appears to be required for maintaining cardiac function [ 75 ]. Data further suggests NR as a favored NAD + precursor in mitochondria [ 76 ], while in vivo NR effects have been interpreted as dependent on mitochondrial sirtuin activities [ 37 , 77 ].…”

Androgen-Regulated Cardiac Metabolism in Aging Men

“…In the heart, the protein sirtuin 3 (SIRT3) is a key regulator of mitochondrial function that adjusts energy availability, fuel sources and metabolic enzymes (164). Abnormal function of SIRT3 in pathophysiological processes is considered as the underlying mechanism of cardiovascular diseases (165)(166)(167)(168). In cardiac cells SIRT3 is a stress-responsive deacetylase that protects these cells from damage induced by genotoxic and oxidative stress-mediated agents.…”

Emerging potential benefits of modulating NAD+metabolism in cardiovascular disease

“…The activity of mitochondrial SIRTs, including SIRT3 and SIRT4, has implications for cardiac remodeling and the development of heart failure. SIRT3 appears to be required for maintaining cardiac function (37). Deficiency of SIRT3 in mice worsened dysfunction in the heart after transverse aortic constriction by impairing cellular bioenergetics through increased acetylation of mitochondrial proteins (18,45).…”