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Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy

Bradley S Ferguson1, Brooke C Harrison, Mark Y Jeong

  • 1Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 31, 2013
PubMed

Insights

Class I histone deacetylase (HDAC) inhibitors suppress cardiac hypertrophy by regulating dual-specificity phosphatase 5 (DUSP5). This mechanism involves a self-reinforcing loop controlling prohypertrophic ERK signaling in heart cells.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Epigenetics

Background:

  • Cardiac hypertrophy is a significant risk factor for heart failure morbidity and mortality.
  • The precise molecular mechanisms by which histone deacetylase (HDAC) inhibitors suppress cardiac hypertrophy are not fully understood.

Purpose of the Study:

  • To elucidate the role of class I HDACs and dual-specificity phosphatase 5 (DUSP5) in regulating cardiac hypertrophy.
  • To investigate the signaling pathways involved in HDAC inhibition-mediated suppression of cardiac hypertrophy.

Main Methods:

  • Utilized selective class I HDAC inhibitors in cardiac myocytes.
  • Investigated the expression and activity of DUSP5 and ERK1/2 signaling pathways.
  • Employed ectopic expression of DUSP5 in cardiomyocytes.

Main Results:

  • Class I HDACs repress cardiac hypertrophy by inhibiting DUSP5 gene expression.
  • DUSP5 acts as a nuclear phosphatase, negatively regulating prohypertrophic ERK1/2 signaling.
  • HDAC inhibition of DUSP5 requires MEK activity, establishing a positive feedback loop for ERK signaling.

Conclusions:

  • Class I HDACs and DUSP5 are key components of a regulatory circuit controlling cardiac hypertrophy.
  • DUSP5 plays a critical role in suppressing agonist-induced cardiac hypertrophy.
  • Targeting this HDAC-DUSP5-ERK pathway may offer therapeutic strategies for heart failure.

Keywords:
cardiac remodelinggene transcriptionlysine acetylation

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