Regulation of cardiac stress signaling by protein kinase d1.
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.
Harrison
Brooke C
BC
Myogen, Inc., 7575 West 103rd Ave., Westminster, Colorado 80021, USA.
Kim
Mi-Sung
MS
van Rooij
Eva
E
Plato
Craig F
CF
Papst
Philip J
PJ
Vega
Rick B
RB
McAnally
John A
JA
Richardson
James A
JA
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
McKinsey
Timothy A
TA
D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020134:Catalytic Domain; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000166:cytology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C; D011494:Protein Kinases / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011920:Rats, Inbred WF; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013312:Stress, Physiological / Q000378:metabolism*
D007527:Isoenzymes; D034741:RNA, Small Interfering; D011494:Protein Kinases; C089212:protein kinase D; D011493:Protein Kinase C