Published Online
on December 27, 2005

A more recent version of this article appeared on January 3, 2006

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Submitted on May 3, 2005
Revised on August 19, 2005
Accepted on October 14, 2005

Inhibition of Histone Deacetylation Blocks Cardiac Hypertrophy Induced by Angiotensin II Infusion and Aortic Banding

Hae Jin Kee PhD, Il Suk Sohn MD, PhD, Kwang Il Nam MD, PhD, Jong Eun Park BS, Yong Ri Qian MD, Zhan Yin PhD, Youngkeun Ahn MD, PhD, Myung Ho Jeong MD, PhD, Yung-Jue Bang MD, PhD, Nacksung Kim PhD, Jong-Keun Kim MD, PhD, Kyung Keun Kim MD, PhD, Jonathan A. Epstein MD, and Hyun Kook MD, PhD^*

From the Departments of Pharmacology (H.J.K., Y.R.Q., J.-K.K., K.K.K., H.K.) and Anatomy (K.I.N.), Research Institute of Medical Sciences and Medical Research Center for Gene Regulation, Chonnam National University Medical School (H.J.K., K.I.N., N.K., K.K.K., H.K.), Gwangju, South Korea; The Heart Center (I.S.S., Y.A., M.H.J.) and Research Institute of Clinical Medicine (J.E.P.) of Chonnam National University Hospital, Gwangju, South Korea; National Research Laboratory for Cancer Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (Y.-J.B.); and Cardiovascular Institute, University of Pennsylvania, Philadelphia (Z.Y., J.A.E.).

^* To whom correspondence should be addressed. E-mail: kookhyun{at}chonnam.ac.kr.

Background--A number of distinct stress signaling pathways in myocardium cause cardiac hypertrophy and heart failure. Class II histone deacetylases (HDACs) antagonize several stress-induced pathways and hypertrophy. However, cardiac hypertrophy induced by transgenic overexpression of the homeodomain only protein, HOP, can be prevented by the nonspecific HDAC inhibitors trichostatin A and valproic acid, suggesting that alternate targets that oppose class II HDAC function might exist in myocardium. We tested the effects of several HDAC inhibitors, including a class I HDAC-selective inhibitor, SK-7041, on cardiac hypertrophy induced by angiotensin II (Ang II) treatment or aortic banding (AB).

Methods and Results--Cardiac hypertrophy was induced by chronic infusion of Ang II or by AB in mice or rats and evaluated by determining the ratio of heart weight to body weight or to tibia length, cross-sectional area, or echocardiogram. Cardiac hypertrophy induced by Ang II or AB for 2 weeks was significantly reduced by simultaneous administration of trichostatin A, valproic acid, or SK-7041. Echocardiogram revealed that exaggerated left ventricular systolic dimensions were relieved by HDAC inhibitors. HDAC inhibitors partially reversed preestablished cardiac hypertrophy and improved survival of AB mice. The expressions of atrial natriuretic factor, -tubulin, -myosin heavy chain, and interstitial fibrosis were reduced by HDAC inhibition.

Conclusions--These results suggest that the predominant effect of HDAC inhibition, mainly mediated by class I HDACs, is to prevent cardiac hypertrophy in response to a broad range of agonist and stretch stimuli.

Key words: angiotensin • aortic banding • histone deacetylases • hypertrophy

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