Regulation of Cardiac Stress Signaling by Protein Kinase D1

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 phosphorylationdependent 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.

Control of endothelial cell proliferation and migration by VEGF signaling to histone deacetylase 7

“…PKD1, also known as protein kinase C (PKC ), is the founding member of a the PKD family, which also includes PKD2 and PKD3/PKC (30). PKD1 has been identified as class IIa HDAC export kinase in cardiomyocytes and thymocytes (29,31,32). PKD has been implicated in diverse processes, such as, vesicular transport, metastasis, immune responses, apoptosis, and cell proliferation (30).…”

Class IIa histone deacetylases: regulating the regulators

“…This is the case for the PKC activator phorbol 13-myristate 12-acetate, for the B-and T-cell receptors and for several other cell surface receptors, such as the serotonin receptor and the G protein-coupled receptors (GPCR) endothelin receptor, a 1 -AR and PGF2a. Signaling via Rho-guanosine triphosphates, mediators of GPCR signaling, and via phospholipase C, a mediator that lies downstream of a 1 -AR, also activates PKD and triggers phosphorylationdependent nuclear export of HDAC5 (Chang et al, 2005;Dequiedt et al, 2005;Harrison et al, 2006). Some of these cell surface receptors also activate calcium fluxes and thus part of their effects could be mediated through activation of CaMKs .…”

A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure

“…Cardiac function and heart dimensions were evaluated by echocardiography as described (34). See Supporting Text for more details.…”