Requirement of protein kinase D1 for pathological cardiac remodeling.
The adult heart responds to biomechanical stress and neurohormonal signaling by hypertrophic growth, accompanied by fibrosis, diminished pump function, and activation of a fetal gene program. Class II histone deacetylases (HDACs) suppress stress-dependent remodeling of the heart via their association with the MEF2 transcription factor, an activator of heart disease. Protein kinase D (PKD) is a stress-responsive kinase that phosphorylates class II HDACs, resulting in their dissociation from MEF2 with consequent activation of MEF2 target genes. To test whether PKD1 is required for pathological cardiac remodeling in vivo, we generated mice with a conditional PKD1-null allele. Mice with cardiac-specific deletion of PKD1 were viable and showed diminished hypertrophy, fibrosis, and fetal gene activation as well as improved cardiac function in response to pressure overload or chronic adrenergic and angiotensin II signaling. We conclude that PKD1 functions as a key transducer of stress stimuli involved in pathological cardiac remodeling in vivo.
Fielitz
Jens
J
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Kim
Mi-Sung
MS
Shelton
John M
JM
Qi
Xiaoxia
X
Hill
Joseph A
JA
Richardson
James A
JA
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
D000818:Animals; D004452:Echocardiography; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics*; D006655:Histone Deacetylases / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D020257:Ventricular Remodeling / Q000235:genetics*
D064326:MEF2 Transcription Factors; C578044:Mef2d protein, mouse; D018006:Myogenic Regulatory Factors; C089212:protein kinase D; D011493:Protein Kinase C; D006655:Histone Deacetylases