Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease

Abstract

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.

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.

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Fig. 1: KAT and KDAC localization in mammalian cells.
Fig. 2: Lysine acetylation-mediated regulation of systemic hypertension and pulmonary arterial hypertension.
Fig. 3: Lysine acetylation-mediated regulation of vascular dysfunction.
Fig. 4: The regulatory role of lysine acetylation in the cardiac cycle and arrhythmia.
Fig. 5: Lysine acetylation in cardiac hypertrophy and fibrosis.
Fig. 6: Lysine acetylation in cardiomyocyte apoptosis, diabetic cardiomyopathy and myocardial IR injury.
Fig. 7: KATs and KDACs regulate VEGF signalling in hypoxia-induced angiogenesis.

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Acknowledgements

The authors thank Q. Qin, D. Xu, Z. Zhao, X. Wang, J. Yang, N. Dai (Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China) and T. Ge (Department of Ophthalmology, Shanghai Tenth People’s Hospital, Shanghai, China) for their constructive suggestions and help with revising the figures. This work was supported by the National Nature Science Foundation of China (81870182, 81521001) and the National Key Basic Research Programme (2016YFC1301204).

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Li, P., Ge, J. & Li, H. Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease. Nat Rev Cardiol 17, 96–115 (2020). https://doi.org/10.1038/s41569-019-0235-9

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