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Molecular and Cellular Biology, October 2004, p. 8467-8476, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8467-8476.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Histone Deacetylases 5 and 9 Govern Responsiveness of the Heart to a Subset of Stress Signals and Play Redundant Roles in Heart Development

Shurong Chang,1,{dagger} Timothy A. McKinsey,2,{dagger} Chun Li Zhang,1 James A. Richardson,1,3 Joseph A. Hill,1,4 and Eric N. Olson1*

Departments of Molecular Biology,1 Pathology,3 Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas,4 Myogen, Inc., Westminster, Colorado2

Received 26 May 2004/ Returned for modification 17 June 2004/ Accepted 10 July 2004

The adult heart responds to stress signals by hypertrophic growth, which is often accompanied by activation of a fetal cardiac gene program and eventual cardiac demise. We showed previously that histone deacetylase 9 (HDAC9) acts as a suppressor of cardiac hypertrophy and that mice lacking HDAC9 are sensitized to cardiac stress signals. Here we report that mice lacking HDAC5 display a similar cardiac phenotype and develop profoundly enlarged hearts in response to pressure overload resulting from aortic constriction or constitutive cardiac activation of calcineurin, a transducer of cardiac stress signals. In contrast, mice lacking either HDAC5 or HDAC9 show a hypertrophic response to chronic ß-adrenergic stimulation identical to that of wild-type littermates, suggesting that these HDACs modulate a specific subset of cardiac stress response pathways. We also show that compound mutant mice lacking both HDAC5 and HDAC9 show a propensity for lethal ventricular septal defects and thin-walled myocardium. These findings reveal central roles for HDACs 5 and 9 in the suppression of a subset of cardiac stress signals as well as redundant functions in the control of cardiac development.

* Corresponding author. Mailing address: Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9148. Phone: (214) 648-1187. Fax: (214) 648-1187. E-mail: eolson{at}hamon.swmed.edu.

{dagger} S.C. and T.A.M. contributed equally.

Molecular and Cellular Biology, October 2004, p. 8467-8476, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8467-8476.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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