The Biology and Therapeutic Implications of HDACs in the Heart

Timothy A. McKinsey

Contents

1 Introduction 58

2 Class Ila HDACs in the Heart 59

2.1 Extranuclear Roles for Class Ila HDACs in the Heart 60

2.2 Signaling to Class Ila HDACs in the Heart 60

3 Class IIb HDACs in the Heart 64

4 Class I HDACs in the Heart 64

5 Class III HDACs in the Heart 65

6 HDAC Inhibitors 66

6.1 Efficacy of HDAC Inhibitors in Preclinical Models of Heart Failure 66

6.2 Translating Preclinical Findings with HDAC Inhibitors to the Clinic 69

7 Conclusions 70

References 70

Abstract The heart responds to stresses such as chronic hypertension and myocardial infarction by undergoing a remodeling process that is associated with myocyte hypertrophy, myocyte death, inflammation and fibrosis, often resulting in impaired cardiac function and heart failure. Recent studies have revealed key roles for histone deacetylases (HDACs) as both positive and negative regulators of pathological cardiac remodeling, and small molecule HDAC inhibitors have demonstrated efficacy in animal models of heart failure. This chapter reviews the functions of individual HDAC isoforms in the heart and highlights issues that need to be addressed to enable development of novel HDAC-directed therapies for cardiovascular indications.

Keywords Histone deacetylase • Heart failure • Signaling • Small molecule inhibitors

Department of Medicine, Division of Cardiology, University of Colorado Denver, 12700 E. 19th Ave, Aurora, CO 80045-0508, USA e-mail: [email protected]

T.-P. Yao and E. Seto (eds.), Histone Deacetylases: the Biology and Clinical Implication, 57 Handbook of Experimental Pharmacology 206, DOI 10.1007/978-3-642-21631-2_4, © Springer-Verlag Berlin Heidelberg 2011

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