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Dose-dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitors
Christopher L Antos1, Timothy A McKinsey, Matthew Dreitz
1Department of Molecular Biology, The University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas 75390-9148, USA.
Insights
Histone deacetylase (HDAC) inhibitors block cardiac hypertrophy and fetal gene activation in cardiomyocytes, suggesting potential therapeutic value for heart failure. Distinct HDACs play opposing roles in regulating cardiac growth.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Epigenetics
Background:
- Postnatal cardiac myocytes undergo hypertrophic growth and activate fetal genes in response to stress.
- Class II histone deacetylases (HDACs) have been shown to suppress cardiac hypertrophy, with HDAC9 deficiency sensitizing mice to hypertrophic signals.
Purpose of the Study:
- To investigate the role of distinct HDACs in cardiac hypertrophy.
- To determine the effects of HDAC inhibitors on cardiomyocyte responsiveness to hypertrophic stimuli.
Main Methods:
- Primary cardiomyocytes were treated with hypertrophic agonists and varying doses of HDAC inhibitors.
- Analysis of hypertrophic growth and fetal gene program activation was performed.
Main Results:
- HDAC inhibitors demonstrated a paradoxical, dose-dependent blockade of both hypertrophy and fetal gene activation in cardiomyocytes.
- These findings indicate that while some HDACs suppress hypertrophy, others may promote it.
Conclusions:
- Distinct HDACs play opposing roles (positive or negative) in the regulation of cardiomyocyte hypertrophy.
- HDAC inhibitors, currently used as anti-cancer agents, may offer therapeutic potential for treating cardiac hypertrophy and heart failure.
Abstract:
Postnatal cardiac myocytes respond to stress signals by hypertrophic growth and activation of a fetal gene program. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy, and mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals. To further define the roles of HDACs in cardiac hypertrophy, we analyzed the effects of HDAC inhibitors on the responsiveness of primary cardiomyocytes to hypertrophic agonists. Paradoxically, HDAC inhibitors imposed a dose-dependent blockade to hypertrophy and fetal gene activation. We conclude that distinct HDACs play positive or negative roles in the control of cardiomyocyte hypertrophy. HDAC inhibitors are currently being tested in clinical trials as anti-cancer agents. Our results suggest that these inhibitors may also hold promising clinical value as therapeutics for cardiac hypertrophy and heart failure.