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Published on: November 2, 2020

Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5

Rick B Vega1, Brooke C Harrison, Eric Meadows

  • 1Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9148, USA.

Molecular and Cellular Biology
|September 16, 2004
PubMed

Insights

Protein kinase C (PKC) and protein kinase D (PKD) signaling promote cardiac hypertrophy by exporting class II histone deacetylases (HDACs) from the nucleus. Inhibiting this pathway may treat pathological cardiac gene expression.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cell Biology
  • Epigenetics

Background:

  • Persistent cardiac hypertrophy increases heart failure risk.
  • Class II histone deacetylases (HDACs) normally suppress cardiac hypertrophy.
  • Stress signals trigger HDAC nuclear export, neutralizing their repressive function.

Purpose of the Study:

  • Identify the kinases responsible for cardiac HDAC nuclear export.
  • Investigate the role of protein kinase C (PKC) and protein kinase D (PKD) in this process.
  • Explore the therapeutic potential of targeting the PKC/PKD pathway in cardiac hypertrophy.

Main Methods:

  • Studied the effect of PKC signaling on HDAC5 nuclear export in cardiomyocytes.
  • Utilized a nonphosphorylatable HDAC5 mutant to assess PKC-dependent phosphorylation.
  • Investigated the direct phosphorylation of HDAC5 by protein kinase D (PKD).

Main Results:

  • PKC signaling is sufficient and sometimes necessary for HDAC5 nuclear export.
  • PKC inhibition blocks HDAC5 nucleocytoplasmic shuttling in response to certain hypertrophic agonists.
  • PKD directly phosphorylates HDAC5, promoting its nuclear export.
  • A nonphosphorylatable HDAC5 mutant prevents PKC-mediated cardiac hypertrophy.

Conclusions:

  • The PKC/PKD signaling axis couples extracellular cues to chromatin modifications controlling cardiac cell growth.
  • PKC/PKD-mediated HDAC5 nuclear export is a key mechanism in pathological cardiac hypertrophy.
  • Inhibitors of the PKC/PKD pathway may offer a therapeutic strategy for cardiac hypertrophy and heart failure.

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