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Molecular and Cellular Biology, May 2006, p. 3875-3888, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3875-3888.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Regulation of Cardiac Stress Signaling by Protein Kinase D1

Brooke C. Harrison,1 Mi-Sung Kim,2 Eva van Rooij,2 Craig F. Plato,1 Philip J. Papst,1 Rick B. Vega,2 John A. McAnally,2 James A. Richardson,2,3 Rhonda Bassel-Duby,2 Eric N. Olson,2* and Timothy A. McKinsey1*

Myogen, Inc., 7575 West 103rd Ave., Westminster, Colorado 80021,1 Department of Molecular Biology,2 Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, Texas 75390-91483

Received 29 August 2005/ Returned for modification 20 October 2005/ Accepted 31 January 2006

In response to pathological stresses such as hypertension or myocardial infarction, the heart undergoes a remodeling process that is associated with myocyte hypertrophy, myocyte death, and fibrosis. Histone deacetylase 5 (HDAC5) is a transcriptional repressor of cardiac remodeling that is subject to phosphorylation-dependent neutralization in response to stress signaling. Recent studies have suggested a role for protein kinase C (PKC) and its downstream effector, protein kinase D1 (PKD1), in the control of HDAC5 phosphorylation. While PKCs are well-documented regulators of cardiac signaling, the function of PKD1 in heart muscle remains unclear. Here, we demonstrate that PKD1 catalytic activity is stimulated in cardiac myocytes by diverse hypertrophic agonists that signal through G protein-coupled receptors (GPCRs) and Rho GTPases. PKD1 activation in cardiomyocytes occurs through PKC-dependent and -independent mechanisms. In vivo, cardiac PKD1 is activated in multiple rodent models of pathological cardiac remodeling. PKD1 activation correlates with phosphorylation-dependent nuclear export of HDAC5, and reduction of endogenous PKD1 expression with small interfering RNA suppresses HDAC5 shuttling and associated cardiomyocyte growth. Conversely, ectopic overexpression of constitutively active PKD1 in mouse heart leads to dilated cardiomyopathy. These findings support a role for PKD1 in the control of pathological remodeling of the heart via its ability to phosphorylate and neutralize HDAC5.

* Corresponding author. Mailing address for Timothy A. McKinsey: Myogen, Inc., 7575 West 103rd Ave., Westminster, CO 80021. Phone: (303) 533-1736. Fax: (303) 410-6669. E-mail: timothy.mckinsey{at}myogen.com. Mailing address for Eric N. Olson: Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9148. Phone: (214) 648-1187. Fax: (214) 648-1196. E-mail: eric.olson{at}utsouthwestern.edu.

Molecular and Cellular Biology, May 2006, p. 3875-3888, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3875-3888.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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