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Increased phosphorylation-dependent nuclear export of class II histone deacetylases in failing human heart

Mihail B Calalb1, Timothy A McKinsey, Scott Newkirk

  • 1University of Colorado Cardiovascular Institute, Denver, USA.

Clinical and Translational Science
|May 7, 2010
PubMed

Insights

In failing human hearts, decreased nuclear HDAC4/5 allows MEF2 activation, driving fetal gene programs in dilated cardiomyopathy. This suggests a key mechanism in heart failure progression.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Heart Failure Pathophysiology

Background:

  • Failing human hearts (FHH) exhibit a fetal gene program linked to dilated cardiomyopathy (DCM).
  • Class II HDACs regulate this program by controlling MEF2 transcription factor activity.
  • Phosphorylation causes nuclear export of Class II HDACs, activating fetal genes.

Purpose of the Study:

  • To investigate if MEF2 activation via Class II HDAC de-repression occurs in FHH.
  • To analyze the levels and activity of MEF2, Class II HDACs (HDAC4, HDAC5), and associated kinases in FHH.

Main Methods:

  • Analysis of human left ventricular tissue from nonfailing and failing adult hearts.
  • Quantification of MEF2, HDAC4, and HDAC5 protein in nuclear fractions.
  • Measurement of CaMK, HDAC kinase, and PKCmu (PKD1) activities.

Main Results:

  • Decreased nuclear HDAC4 and HDAC5 protein in failing ventricles compared to controls.
  • MEF2 levels were not reduced in nuclear fractions from failing hearts.
  • Increased CaMK, HDAC kinase, and PKCmu (PKD1) activities in failing hearts.

Conclusions:

  • Data support reduced nuclear Class II HDACs in FHH.
  • Increased kinase activity correlates with phosphorylation of Class II HDACs, promoting MEF2-dependent fetal gene activation.
  • This mechanism contributes to the DCM phenotype in heart failure.

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