This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 113/22/2579    most recent CIRCULATIONAHA.106.625467v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kong, Y. Articles by Hill, J. A. Search for Related Content PubMed PubMed Citation Articles by Kong, Y. Articles by Hill, J. A. Related Collections Congestive Animal models of human disease Heart failure - basic studies Hypertrophy Physiological and pathological control of gene expression

(Circulation. 2006;113:2579-2588.)
© 2006 American Heart Association, Inc.

Heart Failure

Suppression of Class I and II Histone Deacetylases Blunts Pressure-Overload Cardiac Hypertrophy

Yongli Kong, MD, PhD; Paul Tannous, BS; Guangrong Lu, MD; Kambeez Berenji, MD; Beverly A. Rothermel, PhD; Eric N. Olson, PhD; Joseph A. Hill, MD, PhD

From the Donald W. Reynolds Cardiovascular Clinical Research Center (E.N.O., J.A.H.) and the Departments of Internal Medicine (Y.K., P.T., G.L., K.B., B.A.R., J.A.H.) and Molecular Biology (E.N.O., J.A.H.), University of Texas Southwestern Medical Center, Dallas.

Correspondence to Joseph A. Hill, MD, PhD, Division of Cardiology, UT Southwestern Medical Center, NB11.200, 6000 Harry Hines Blvd, Dallas, TX 75390–8573. E-mail joseph.hill{at}UTSouthwestern.edu

Received November 21, 2005; de novo received March 7, 2006; revision received April 1, 2006; accepted April 7, 2006.

Background— Recent work has demonstrated the importance of chromatin remodeling, especially histone acetylation, in the control of gene expression in the heart. In cell culture models of cardiac hypertrophy, pharmacological suppression of histone deacetylases (HDACs) can either blunt or amplify cell growth. Thus, HDAC inhibitors hold promise as potential therapeutic agents in hypertrophic heart disease.

Methods and Results— In the present investigation, we studied 2 broad-spectrum HDAC inhibitors in a physiologically relevant banding model of hypertrophy, observing dose-responsive suppression of ventricular growth that was well tolerated in terms of both clinical outcome and cardiac performance measures. In both short-term (3-week) and long-term (9-week) trials, cardiomyocyte growth was blocked by HDAC inhibition, with no evidence of cell death or apoptosis. Fibrotic change was diminished in hearts treated with HDAC inhibitors, and collagen synthesis in isolated cardiac fibroblasts was blocked. Preservation of systolic function in the setting of blunted hypertrophic growth was documented by echocardiography and by invasive pressure measurements. The hypertrophy-associated switch of adult and fetal isoforms of myosin heavy chain expression was attenuated, which likely contributed to the observed preservation of systolic function in HDAC inhibitor–treated hearts.

Conclusions— Together, these data suggest that HDAC inhibition is a viable therapeutic strategy that holds promise in the treatment of load-induced heart disease.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				J. Q. Wei, L. A. Shehadeh, J. M. Mitrani, M. Pessanha, T. I. Slepak, K. A. Webster, and N. H. Bishopric Quantitative Control of Adaptive Cardiac Hypertrophy by Acetyltransferase p300 Circulation, August 26, 2008; 118(9): 934 - 946. [Abstract] [Full Text] [PDF]

				H. Su, L. Altucci, and Q. You Competitive or noncompetitive, that's the question: research toward histone deacetylase inhibitors Mol. Cancer Ther., May 1, 2008; 7(5): 1007 - 1012. [Abstract] [Full Text] [PDF]

				M. P. Gupta, S. A. Samant, S. H. Smith, and S. G. Shroff HDAC4 and PCAF Bind to Cardiac Sarcomeres and Play a Role in Regulating Myofilament Contractile Activity J. Biol. Chem., April 11, 2008; 283(15): 10135 - 10146. [Abstract] [Full Text] [PDF]

				J. G. Edwards Cardiac MHC gene expression: more complexity and a step forward Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H14 - H15. [Full Text] [PDF]

				T. C. Zhao, G. Cheng, L. X. Zhang, Y. T. Tseng, and J. F. Padbury Inhibition of histone deacetylases triggers pharmacologic preconditioning effects against myocardial ischemic injury Cardiovasc Res, December 1, 2007; 76(3): 473 - 481. [Abstract] [Full Text] [PDF]

				R. L. Montgomery, C. A. Davis, M. J. Potthoff, M. Haberland, J. Fielitz, X. Qi, J. A. Hill, J. A. Richardson, and E. N. Olson Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility Genes & Dev., July 15, 2007; 21(14): 1790 - 1802. [Abstract] [Full Text] [PDF]

				T. A. McKinsey Derepression of pathological cardiac genes by members of the CaM kinase superfamily Cardiovasc Res, March 1, 2007; 73(4): 667 - 677. [Abstract] [Full Text] [PDF]

				A. Diwan and G. W. Dorn II Decompensation of Cardiac Hypertrophy: Cellular Mechanisms and Novel Therapeutic Targets Physiology, February 1, 2007; 22(1): 56 - 64. [Abstract] [Full Text] [PDF]