Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy

被引:316
作者
Kong, Yongli
Tannous, Paul
Lu, Guangrong
Berenji, Kambeez
Rothermel, Beverly A.
Olson, Eric N.
Hill, Joseph A.
机构
[1] Univ Texas, SW Med Ctr, Div Cardiol, Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX 75390 USA
[3] Univ Texas, SW Med Ctr, Dept Mol Biol, Dallas, TX 75390 USA
关键词
hypertrophy; signal transduction; chromatin remodeling; histone deacetylases;
D O I
10.1161/CIRCULATIONAHA.106.625467
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:2579 / 2588
页数:10
相关论文
共 33 条
[1]   Silent information regulator 2α, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes [J].
Alcendor, RR ;
Kirshenbaum, LA ;
Imai, S ;
Vatner, SF ;
Sadoshima, J .
CIRCULATION RESEARCH, 2004, 95 (10) :971-980
[2]   Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo [J].
Antos, CL ;
McKinsey, TA ;
Frey, N ;
Kutschke, W ;
McAnally, J ;
Shelton, JM ;
Richardson, JA ;
Hill, JA ;
Olson, EN .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (02) :907-912
[3]   Dose-dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitors [J].
Antos, CL ;
McKinsey, TA ;
Dreitz, M ;
Hollingsworth, LM ;
Zhang, CL ;
Schreiber, K ;
Rindt, H ;
Gorczynski, RJ ;
Olson, EN .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (31) :28930-28937
[4]   Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases [J].
Brush, MH ;
Guardiola, A ;
Connor, JH ;
Yao, TP ;
Shenolikar, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (09) :7685-7691
[5]   Concentric versus eccentric remodeling [J].
Carabello, BA .
JOURNAL OF CARDIAC FAILURE, 2002, 8 (06) :S258-S263
[6]   Hypertrophy of the heart - A new therapeutic target? [J].
Frey, N ;
Katus, HA ;
Olson, EN ;
Hill, JA .
CIRCULATION, 2004, 109 (13) :1580-1589
[7]   The transcriptional co-activators CREB-binding protein (CBP) and p300 play a critical role in cardiac hypertrophy that is dependent on their histone acetyltransferase activity [J].
Gusterson, RJ ;
Jazrawi, E ;
Adcock, IM ;
Latchman, DS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (09) :6838-6847
[8]   Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2 [J].
Han, AD ;
Pan, F ;
Stroud, JC ;
Youn, HD ;
Liu, JO ;
Chen, L .
NATURE, 2003, 422 (6933) :730-734
[9]   Small amounts of α-myosin heavy chain isoform expression significantly increase power output of rat cardiac myocyte fragments [J].
Herron, TJ ;
McDonald, KS .
CIRCULATION RESEARCH, 2002, 90 (11) :1150-1152
[10]   Cardiac hypertrophy is not a required compensatory response to short-term pressure overload [J].
Hill, JA ;
Karimi, M ;
Kutschke, W ;
Davisson, RL ;
Zimmerman, K ;
Wang, ZY ;
Kerber, RE ;
Weiss, RM .
CIRCULATION, 2000, 101 (24) :2863-2869