Regulation of cardiac stress signaling by protein kinase D1

Brooke C. Harrison, Mi Sung Kim, Eva Van Rooij, Craig F. Plato, Philip J. Papst, Rick B. Vega, John A. McAnally, James A. Richardson, Rhonda Bassel-Duby, Eric N. Olson, Timothy A. McKinsey

Research output: Contribution to journalArticle

120 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3875-3888
Number of pages14
JournalMolecular and Cellular Biology
Volume26
Issue number10
DOIs
Publication statusPublished - May 2006

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Harrison, B. C., Kim, M. S., Van Rooij, E., Plato, C. F., Papst, P. J., Vega, R. B., ... McKinsey, T. A. (2006). Regulation of cardiac stress signaling by protein kinase D1. Molecular and Cellular Biology, 26(10), 3875-3888. https://doi.org/10.1128/MCB.26.10.3875-3888.2006