Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease

• Published in: Nature reviews cardiology Vol. 17; no. 2; pp. 96 - 115
• Main Authors: Li, Peng, Ge, Junbo, Li, Hua
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2020; Nature Publishing Group
• Subjects: 692/4019/592/75; 692/700/565/1436/152; Acetylation; Angiogenesis; Animals; Atherosclerosis; Blood pressure; Cardiac arrhythmia; Cardiac Imaging; Cardiac Surgery; Cardiology; Cardiovascular Agents - therapeutic use; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - diagnosis; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - enzymology; Cardiovascular Diseases - physiopathology; Cardiovascular research; Cardiovascular System - drug effects; Cardiovascular System - enzymology; Cardiovascular System - physiopathology; Care and treatment; Development and progression; Enzyme inhibitors; Enzymes; Gene expression; Health aspects; Heart failure; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - metabolism; Humans; Hypertension; Lymphocytes; Lymphoma; Lysine; Lysine Acetyltransferases - antagonists & inhibitors; Lysine Acetyltransferases - metabolism; Medicine; Medicine & Public Health; Molecular Targeted Therapy; Physiological aspects; Post-translational modification; Protein Processing, Post-Translational - drug effects; Proteins; Regulatory approval; Review Article; RNA polymerase; Roles; Signal Transduction; Transferases; China
• ISSN: 1759-5002; 1759-5010
• DOI: 10.1038/s41569-019-0235-9

Lysine acetylation is a conserved, reversible, post-translational protein modification regulated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs; also known as histone deacetylases (HDACs)) that is involved in many cellular signalling pathways and diseases. Studies in animal models have revealed a regulatory role of reversible lysine acetylation in hypertension, vascular diseases, arrhythmia, heart failure and angiogenesis. Evidence from these studies indicates a therapeutic role of KDAC inhibitors (also known as HDAC inhibitors) in cardiovascular diseases. In this Review, we describe the diverse roles of KATs and KDACs in both the normal and the diseased heart. Among KDACs, class II and class III HDACs seem to have a protective role against both cardiac damage and vessel injury, whereas class I HDACs protect against vessel injury but have deleterious effects on the heart. These observations have important implications for the clinical utility of HDAC inhibitors as therapeutic agents for cardiovascular diseases. In addition, we summarize the latest data on nonacetylation acylations in the context of cardiovascular disease. Lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) are involved in the regulation of lysine acetylation, a conserved post-translational protein modification that is an important modulator of cardiac metabolism. Li and colleagues describe the complex roles of KATs and KDACs in both the normal and diseased heart and provide an overview of the evidence indicating a therapeutic role of KDAC inhibitors in cardiovascular disease. Key points Reversible lysine acetylation mediated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) has an important role in the development of cardiovascular diseases (CVDs). The pathophysiological processes underlying CVD, including risk factor development, early pathological events (such as atherosclerosis), end-stage events (such as heart failure) and recovery-stage events (such as ischaemia–reperfusion injury and angiogenesis), are regulated by lysine acetylation. The regulation of lysine acylation in CVD development varies according to metabolic conditions or disease stages. Class II and class III histone deacetylases (HDACs) have protective roles not only in heart injury but also in vessel injury, whereas class I HDACs protect against vessel damage but are harmful to the myocardium. Unlike other HDAC inhibitors (HDACis), class I HDACis have been shown to cause arrhythmias, atherosclerosis and vessel calcification. Owing to a reduced likelihood of adverse effects, isoform-selective HDACis, tissue-specific HDACis and sirtuin activators might have clinical value in the treatment of CVDs.