Cardiac Acetylation in Metabolic Diseases

Abstract

Lysine acetylation is a highly conserved mechanism that affects several biological processes such as cell growth, metabolism, enzymatic activity, subcellular localization of proteins, gene transcription or chromatin structure. This post-translational modification, mainly regulated by lysine acetyltransferase (KAT) and lysine deacetylase (KDAC) enzymes, can occur on histone or non-histone proteins. Several studies have demonstrated that dysregulated acetylation is involved in cardiac dysfunction, associated with metabolic disorder or heart failure. Since the prevalence of obesity, type 2 diabetes or heart failure rises and represents a major cause of cardiovascular morbidity and mortality worldwide, cardiac acetylation may constitute a crucial pathway that could contribute to disease development. In this review, we summarize the mechanisms involved in the regulation of cardiac acetylation and its roles in physiological conditions. In addition, we highlight the effects of cardiac acetylation in physiopathology, with a focus on obesity, type 2 diabetes and heart failure. This review sheds light on the major role of acetylation in cardiovascular diseases and emphasizes KATs and KDACs as potential therapeutic targets for heart failure.

Keywords: acetylation; diabetes; enzymes; heart; heart failure; obesity.

Figure 1

Subcellular localization of cardiac KATs and KDACs. This figure summarizes the subcellular localization of the most common lysine acetyltransferases (KATs, blue) and lysine deacetylases (KDAC, orange) and their cardiac targets. Ac: acetylated form; HDAC: histone deacetylase; SIRT: sirtuins; β-MHC: beta-myosin heavy chain; TnI: Troponin I; prx1: peroxiredoxin 1; LCAD: long chain acyl CoA dehydrogenase; SCAD: short chain acyl CoA dehydrogenase; β-HAD: L-3-hydroxy acyl-CoA dehydrogenase; SOD2: superoxide dismutase 2; CypD: Cyclophilin D; OPA1: optic atrophic 1; TBX5: T-Box transcription factor 5; VGLL4: vestigial-like 4; GATA4: GATA-binding factor 4; MEF: myocyte enhancer factor; Nrf2: nuclear factor erythroid-2-related factor 2; GCN5L1: general control of amino acid synthesis 5 like-1; CBP: CREB binding protein.

Figure 2

Physiological roles of cardiac acetylation. Ac: acetylated form; KATs: lysine acetyltransferases; KDACs: lysine deacetylase; ROS: reactive oxygen species.