Cardiac hypertrophy and histone deacetylase–dependent transcriptional repression mediated by the atypical homeodomain protein Hop
Hyun Kook, John J. Lepore, Aaron D. Gitler, Min Min Lu, Wendy Wing-Man Yung, Joel Mackay, Rong Zhou, Victor Ferrari, Peter Gruber, Jonathan A. Epstein
Hyun Kook, John J. Lepore, Aaron D. Gitler, Min Min Lu, Wendy Wing-Man Yung, Joel Mackay, Rong Zhou, Victor Ferrari, Peter Gruber, Jonathan A. Epstein
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Article Cardiology

Cardiac hypertrophy and histone deacetylase–dependent transcriptional repression mediated by the atypical homeodomain protein Hop

Abstract

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. Repression of antihypertrophic pathways has rarely been demonstrated to cause cardiac hypertrophy in vivo. Hop is an unusual homeodomain protein that is expressed by embryonic and postnatal cardiac myocytes. Unlike other homeodomain proteins, Hop does not bind DNA. Rather, it modulates cardiac growth and proliferation by inhibiting the transcriptional activity of serum response factor (SRF) in cardiomyocytes. Here we show that Hop can inhibit SRF-dependent transcriptional activation by recruiting histone deacetylase (HDAC) activity and can form a complex that includes HDAC2. Transgenic mice that overexpress Hop develop severe cardiac hypertrophy, cardiac fibrosis, and premature death. A mutant form of Hop, which does not recruit HDAC activity, does not induce hypertrophy. Treatment of Hop transgenic mice with trichostatin A, an HDAC inhibitor, prevents hypertrophy. In addition, trichostatin A also attenuates hypertrophy induced by infusion of isoproterenol. Thus, chromatin remodeling and repression of otherwise active transcriptional processes can result in hypertrophy and heart failure, and this process can be blocked with chemical HDAC inhibitors.

Authors

Hyun Kook, John J. Lepore, Aaron D. Gitler, Min Min Lu, Wendy Wing-Man Yung, Joel Mackay, Rong Zhou, Victor Ferrari, Peter Gruber, Jonathan A. Epstein

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Treatment with HDAC inhibitor prevents cardiac hypertrophy in Hop transg...
Treatment with HDAC inhibitor prevents cardiac hypertrophy in Hop transgenic mice. (a) HDAC activity was associated with immunoprecipitated transgenic Hop protein derived from hearts of transgenic Hop mice (5–6 weeks of age) when compared with wild-type littermates. (b) Transgenic and wild-type littermates were treated with daily injections of TSA between the ages of 3 and 5 weeks. Heart weight–to–body weight ratios were calculated at 5 weeks. Bars indicate mean of values shown, and each filled circle represents one animal. TSA significantly attenuated cardiac hypertrophy, but did not affect heart weight–to–body weight ratio in nontransgenic mice. (c) Hop transgenic mice were also treated with sodium valproate between 3 and 5 weeks of age, which resulted in attenuation of cardiac enlargement at 5 weeks. (d) Wild-type mice were treated with isoproterenol (ISO) infusion between 3 and 5 weeks of life, with or without daily injection of TSA. Heart weight–to–body weight ratio increased significantly with isoproterenol, and this increase was significantly inhibited by TSA. (e) Model depicting the ability of Hop or other hypertrophic stimuli to recruit class I HDACs resulting in inhibition of antihypertrophic gene programs. Inducers of cardiac hypertrophy are also thought to function by altering calcium homeostasis or mechanical stretch and induce prohypertrophic genes. Class II HDACs can inhibit some prohypertrophic programs. The relative balance of pro- and antihypertrophic gene programs will determine the extent of myocyte hypertrophy.