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.
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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Hypertension | 2009 |
Curcumin Prevents and Reverses Cardiac Hypertrophy
Hong-Liang Li, Chen Liu, Geoffrey de Couto, Maral Ouzounian, Mei Sun, Ai-Bing Wang, Yue Huang, Cheng-Wei He, Yu Shi, Xin Chen, Mai P. Nghiem, Youan Liu, Manyin Chen, Fayez Dawood, Masahiro Fukuoka, Yuichiro Maekawa, Liyong Zhang, Andrew Leask, Asish K. Ghosh, Lorrie A. Kirshenbaum, Peter. P Liu |
Journal of Clinical Investigation | 2008 |
Currying favor for the heart
Jonathan A. Epstein |
Journal of Clinical Investigation | 2008 |
Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis
PH Sugden, SJ Fuller, SC Weiss, A Clerk |
British Journal of Pharmacology | 2008 |
A new (heat) shocking player in cardiac hypertrophy
TM Vondriska, Y Wang |
Circulation research | 2008 |
Epigenetic regulation of cardiac muscle-specific genes in H9c2 cells by Interleukin-18 and histone deacetylase inhibitor m-carboxycinnamic acid bis-hydroxamide
G Majumdar, IM Johnson, S Kale, R Raghow |
Molecular and Cellular Biochemistry | 2008 |
Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin
F Liu, MD Levin, NB Petrenko, MM Lu, T Wang, LJ Yuan, AL Stout, JA Epstein, VV Patel |
Journal of Molecular and Cellular Cardiology | 2008 |
Transgenic Overexpression of Hdac3 in the Heart Produces Increased Postnatal Cardiac Myocyte Proliferation but Does Not Induce Hypertrophy
CM Trivedi, MM Lu, Q Wang, JA Epstein |
The Journal of biological chemistry | 2008 |
TGFbeta inducible early gene-1 (TIEG1) and cardiac hypertrophy: Discovery and characterization of a novel signaling pathway
NM Rajamannan, M Subramaniam, TP Abraham, VC Vasile, MJ Ackerman, DG Monroe, TL Chew, TC Spelsberg |
Journal of Cellular Biochemistry | 2007 |
Re-employment of developmental transcription factors in adult heart disease
T Oka, J Xu, JD Molkentin |
Seminars in Cell & Developmental Biology | 2007 |
Epigenetic abnormalities in cardiac hypertrophy and heart failure
H Mano |
Environmental Health and Preventive Medicine | 2007 |
Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity
A Rephaeli, S Waks-Yona, A Nudelman, I Tarasenko, N Tarasenko, DR Phillips, SM Cutts, G Kessler-Icekson |
British Journal of Cancer | 2007 |
Control of SRF binding to CArG-box chromatin regulates smooth muscle gene expression in vivo
Oliver G. McDonald, Brian R. Wamhoff, Mark H. Hoofnagle, Gary K. Owens |
Journal of Clinical Investigation | 2006 |
Transcription factor CHF1/Hey2 suppresses cardiac hypertrophy through an inhibitory interaction with GATA4
F Xiang, Y Sakata, L Cui, JM Youngblood, H Nakagami, JK Liao, R Liao, MT Chin |
American journal of physiology. Heart and circulatory physiology | 2006 |
Recent insights into cardiac hypertrophy and left ventricular remodeling
R Kerkela, T Force |
Current Heart Failure Reports | 2006 |
Role of homeodomain-only protein in the cardiac conduction system
F Liu, FA Ismat, VV Patel |
Trends in Cardiovascular Medicine | 2006 |
Suppression of Class I and II Histone Deacetylases Blunts Pressure-Overload Cardiac Hypertrophy
Y Kong, P Tannous, G Lu, K Berenji, BA Rothermel, EN Olson, JA Hill |
Circulation | 2006 |
Changes in skeletal muscle gene expression following clenbuterol administration
DM Spurlock, TG McDaneld, LM McIntyre |
BMC Genomics | 2006 |
Genetic causes of human heart failure
H Morita, J Seidman, CE Seidman |
Journal of Clinical Investigation | 2005 |
Toward transcriptional therapies for the failing heart: chemical screens to modulate genes
TA McKinsey, EN Olson |
Journal of Clinical Investigation | 2005 |
Homeobox Protein Hop Functions in the Adult Cardiac Conduction System
FA Ismat, M Zhang, H Kook, B Huang, R Zhou, VA Ferrari, JA Epstein, VV Patel |
Circulation research | 2005 |
Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development
S Chang, TA McKinsey, CL Zhang, JA Richardson, JA Hill, EN Olson |
Molecular and cellular biology | 2004 |
Muscle ring finger protein-1 inhibits PKCε activation and prevents cardiomyocyte hypertrophy
R Arya, V Kedar, JR Hwang, H McDonough, HH Li, J Taylor, C Patterson |
The Journal of Cell Biology | 2004 |
HATs off to Hop: recruitment of a class I histone deacetylase incriminates a novel transcriptional pathway that opposes cardiac hypertrophy
Y Hamamori, MD Schneider |
Journal of Clinical Investigation | 2003 |