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(Circulation. 2006;113:51-59.)
© 2006 American Heart Association, Inc.

Heart Failure

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; 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.).

Correspondence to Hyun Kook, MD, PhD, 5 Hak-dong, Dong-ku, Gwangju 501-746, South Korea (e-mail kookhyun{at}chonnam.ac.kr) or Jonathan A. Epstein, MD, 954 BRB II, 421 Curie Blvd, Philadelphia, PA 19104 (e-mail epsteinj@mail.med.upenn.edu).

Received May 3, 2005; revision received August 19, 2005; accepted October 14, 2005.

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, ß-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.

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