Roles and Targets of Class I and IIa Histone Deacetylases in Cardiac Hypertrophy

Hae Jin Kee,Hyun Kook

doi:10.1155/2011/928326

Abstract

Cardiac hypertrophy occurs in association with heart diseases and ultimately results in cardiac dysfunction and heart failure. Histone deacetylases (HDACs) are post-translational modifying enzymes that can deacetylate histones and non-histone proteins. Research with HDAC inhibitors has provided evidence that the class I HDACs are pro-hypertrophic. Among the class I HDACs, HDAC2 is activated by hypertrophic stresses in association with the induction of heat shock protein 70. Activated HDAC2 triggers hypertrophy by inhibiting the signal cascades of either Krüppel like factor 4 (KLF4) or inositol polyphosphate-5-phosphatase f (Inpp5f). Thus, modulators of HDAC2 enzymes, such as selective HDAC inhibitors, are considered to be an important target for heart diseases, especially for preventing cardiac hypertrophy. In contrast, class IIa HDACs have been shown to repress cardiac hypertrophy by inhibiting cardiac-specific transcription factors such as myocyte enhancer factor 2 (MEF2), GATA4, and NFAT in the heart. Studies of class IIa HDACs have shown that the underlying mechanism is regulated by nucleo-cytoplasm shuttling in response to a variety of stress signals. In this review, we focus on the class I and IIa HDACs that play critical roles in mediating cardiac hypertrophy and discuss the non-histone targets of HDACs in heart disease.

Highlights

Cardiac hypertrophy is an adaptive response to an initial exogenous hypertrophic stimulus that leads to a maladaptive state when the stress is prolonged [1]
We demonstrated that class I Histone deacetylases (HDACs) are required for the hypertrophic response in aortic banding or angiotensin II infusion-induced hypertrophy animal models with class I HDAC-selective HDAC inhibitor
Considering that class II HDACs work as antihypertrophic mediators, prevention of cardiac hypertrophy with nonspecific HDAC inhibitors strongly suggests that class I HDAC may function as a pro-hypertrophic regulator in the heart

Summary

Introduction

Cardiac hypertrophy is an adaptive response to an initial exogenous hypertrophic stimulus that leads to a maladaptive state when the stress is prolonged [1]. Cardiac hypertrophy is characterized by increased cell size, enhanced protein synthesis, and heightened organization of the sarcomere. Immediate-early genes encoding c-fos, c-jun, and heat shock proteins are upregulated [3, 4] In humans, stresses such as chronic hypertension and myocardial infarction can trigger the heart to undergo remodeling processes characterized by myocyte hypertrophy, myocyte death, and fibrosis, often resulting in pathological heart diseases including reduced cardiac function, cardiomyopathy, and heart failure [5,6,7,8]. Many HDACs have a highly conserved domain, recent studies show that class I and IIa HDACs have opposing roles in regulating cardiac hypertrophy, and evidence for the mechanisms by which the distinct classes of HDACs act to control cardiac hypertrophy is growing. We focus on the pathophysiological roles of class I and IIa HDACs in cardiac hypertrophy

Heart Diseases Regulated by Class I HDACs

Class III HDACs

Deacetylation of Nonhistone Proteins by HDACs

Summary and Further Suggestions