Cardiac hypertrophy and histone deacetylase–dependent transcriptional repression mediated by the atypical homeodomain protein Hop
Hyun Kook, … , Peter Gruber, Jonathan A. Epstein
Hyun Kook, … , Peter Gruber, Jonathan A. Epstein
Published September 15, 2003
Citation Information: J Clin Invest. 2003;112(6):863-871. https://doi.org/10.1172/JCI19137.
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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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Early lethality and cardiac hypertrophy induced by Hop, but not by mutan...
Early lethality and cardiac hypertrophy induced by Hop, but not by mutant HopH2. (a) Kaplan-Meier plot revealing reduced survival of Hop transgenic mice (TgHop wt) compared with wild-type and HopH2 transgenic mice (TgHop H2). (b) Cardiac hypertrophy in Hop transgenic mice is progressive. Heart weight–to–body weight ratios were calculated at various ages, as indicated, and expressed as percentage of change compared with wild-type littermates. Values from two independent transgenic lines are pooled and each bar represents the average of 8–16 data points. Error bars represent SEM. *P < 0.05 compared with wild type. (c) Circular dichroism analysis of Hop and HopH2 protein indicates similar conformations and α helicity of wild-type Hop and HopH2 mutant proteins. (θ)MRW, mean residue weight ellipticity. (d). Heart weight–to–body weight ratios of Hop transgenic mice, four independent lines of HopH2 transgenic mice, and Hop knockout mice between 4 and 8 weeks of age. Between 10 and 25 animals were assayed for each condition. No significant difference between transgenic and nontransgenic littermates was determined for HopH2 mice or for Hop–/– mice. Western blot analysis of heart tissue using anti-hemagglutinin (HA) antibody revealing expression of transgenic protein is also shown. Line numbers refer to independent transgenic lines. (e) Immunohistochemistry identifies nuclear epitope-tagged Hop protein in transgenic hearts (red). (f) HopH2 is also nuclear localized in transgenic hearts. Scale bars in e and f: 20 μm.