Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy

Yongli Kong, Paul Tannous, Guangrong Lu, Kambeez Berenji, Beverly A Rothermel, Eric N Olson, Joseph A Hill

Research output: Contribution to journalArticle

250 Scopus citations

Abstract

BACKGROUND - Recent work has demonstrated the importance of chromatin remodeling, especially histone acetylation, in the control of gene expression in the heart. In cell culture models of cardiac hypertrophy, pharmacological suppression of histone deacetylases (HDACs) can either blunt or amplify cell growth. Thus, HDAC inhibitors hold promise as potential therapeutic agents in hypertrophic heart disease. METHODS AND RESULTS - In the present investigation, we studied 2 broad-spectrum HDAC inhibitors in a physiologically relevant banding model of hypertrophy, observing dose-responsive suppression of ventricular growth that was well tolerated in terms of both clinical outcome and cardiac performance measures. In both short-term (3-week) and long-term (9-week) trials, cardiomyocyte growth was blocked by HDAC inhibition, with no evidence of cell death or apoptosis. Fibrotic change was diminished in hearts treated with HDAC inhibitors, and collagen synthesis in isolated cardiac fibroblasts was blocked. Preservation of systolic function in the setting of blunted hypertrophic growth was documented by echocardiography and by invasive pressure measurements. The hypertrophy-associated switch of adult and fetal isoforms of myosin heavy chain expression was attenuated, which likely contributed to the observed preservation of systolic function in HDAC inhibitor-treated hearts. CONCLUSIONS - Together, these data suggest that HDAC inhibition is a viable therapeutic strategy that holds promise in the treatment of load-induced heart disease.

Original languageEnglish (US)
Pages (from-to)2579-2588
Number of pages10
JournalCirculation
Volume113
Issue number22
DOIs
StatePublished - Jun 1 2006

Keywords

  • Chromatin remodeling
  • Histone deacetylases
  • Hypertrophy
  • Signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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