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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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Article Cardiology

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

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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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Figure 1

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Transgenic expression of Hop in the heart causes cardiac hypertrophy. (a...
Transgenic expression of Hop in the heart causes cardiac hypertrophy. (a) Wild-type (left) and Hop transgenic (Tg) hearts at 8 weeks of age are shown. Scale bar: 1 mm. (b) Heart weight–to–body weight ratios of Hop transgenic (black bars) and wild-type littermate (white bars) mice between 5 and 10 weeks of age are shown. Hop transgenic hearts are significantly enlarged. (c) M-mode echocardiography demonstrates thickened myocardial walls in transgenic mice (red arrows) and hyperdynamic function with cavity obliteration. (d) EKG-gated cardiac MRI reveals cardiac hypertrophy. Short-axis view images were captured during end diastole showing high contrast between blood (appearing bright) and myocardium. (e) Mason’s trichrome staining of myocardium from wild-type 28-week-old mouse reveals normal cardiac histology. (f) Identical staining technique and magnification of Hop transgenic littermate reveals massive myocyte hypertrophy and significant interstitial fibrosis (blue). (e and f) Scale bars: 50 μm.

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