Requirement of protein kinase D1 for pathological cardiac remodeling

Jens Fielitz, Mi Sung Kim, John M. Shelton, Xiaoxia Qi, Joseph A Hill, James A Richardson, Rhonda S Bassel-Duby, Eric N Olson

Research output: Contribution to journalArticle

147 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3059-3063
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number8
DOIs
StatePublished - Feb 26 2008

Fingerprint

Histone Deacetylases
Protein Kinases
Fibrosis
MEF2 Transcription Factors
Transducers
Angiotensin II
Adrenergic Agents
Hypertrophy
Transcriptional Activation
Genes
Heart Diseases
Phosphotransferases
Alleles
Pressure
Growth
protein kinase D

Keywords

  • Cardiac hypertrophy
  • Histone deacetylase
  • Stress-responsive kinase

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Requirement of protein kinase D1 for pathological cardiac remodeling. / Fielitz, Jens; Kim, Mi Sung; Shelton, John M.; Qi, Xiaoxia; Hill, Joseph A; Richardson, James A; Bassel-Duby, Rhonda S; Olson, Eric N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 8, 26.02.2008, p. 3059-3063.

Research output: Contribution to journalArticle

@article{c4f4ab848bf048e887f349ce74c618a4,
title = "Requirement of protein kinase D1 for pathological cardiac remodeling",
abstract = "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.",
keywords = "Cardiac hypertrophy, Histone deacetylase, Stress-responsive kinase",
author = "Jens Fielitz and Kim, {Mi Sung} and Shelton, {John M.} and Xiaoxia Qi and Hill, {Joseph A} and Richardson, {James A} and Bassel-Duby, {Rhonda S} and Olson, {Eric N}",
year = "2008",
month = "2",
day = "26",
doi = "10.1073/pnas.0712265105",
language = "English (US)",
volume = "105",
pages = "3059--3063",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "8",

}

TY - JOUR

T1 - Requirement of protein kinase D1 for pathological cardiac remodeling

AU - Fielitz, Jens

AU - Kim, Mi Sung

AU - Shelton, John M.

AU - Qi, Xiaoxia

AU - Hill, Joseph A

AU - Richardson, James A

AU - Bassel-Duby, Rhonda S

AU - Olson, Eric N

PY - 2008/2/26

Y1 - 2008/2/26

N2 - 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.

AB - 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.

KW - Cardiac hypertrophy

KW - Histone deacetylase

KW - Stress-responsive kinase

UR - http://www.scopus.com/inward/record.url?scp=42949099439&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42949099439&partnerID=8YFLogxK

U2 - 10.1073/pnas.0712265105

DO - 10.1073/pnas.0712265105

M3 - Article

VL - 105

SP - 3059

EP - 3063

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 8

ER -