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Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity
Chinmay M Trivedi1, Yang Luo, Zhan Yin
1Department of Cell and Developmental Biology, 1156 Basic Research Building II, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
Nature Medicine
|February 27, 2007
Summary
Histone deacetylase-2 (Hdac2) regulates fetal gene expression in the adult heart. Inhibiting Hdac2 or its targets prevents cardiac hypertrophy, offering a potential therapeutic strategy for heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Epigenetics
Background:
- Adult heart stress can trigger a fetal gene program, leading to myocyte hypertrophy and heart failure.
- Histone deacetylase-2 (Hdac2) plays a role in regulating fetal gene expression in cardiac cells.
Purpose of the Study:
- To investigate the role of Hdac2 in cardiac hypertrophy and heart failure.
- To explore Hdac2 as a potential therapeutic target for cardiac diseases.
Main Methods:
- Utilized Hdac2-deficient and Hdac2 transgenic mouse models.
- Administered chemical histone deacetylase (HDAC) inhibitors and Gsk3beta inhibitors.
- Analyzed gene expression, including fetal cardiac isoforms, Inpp5f, Akt, and Pdk1.
Main Results:
- Hdac2 deficiency or HDAC inhibition prevented fetal gene re-expression and attenuated cardiac hypertrophy.
- Hdac2 deficiency led to increased Inpp5f expression, activating Gsk3beta.
- Hdac2 transgenic mice showed augmented hypertrophy with inactivated Gsk3beta.
- Inhibition of Gsk3beta in Hdac2-deficient mice restored sensitivity to hypertrophic stimuli.
Conclusions:
- Hdac2 is a key regulator of fetal gene expression and cardiac hypertrophy in the adult heart.
- Hdac2 and Gsk3beta form a regulatory pathway relevant to cardiac hypertrophy.
- Hdac2 is a molecular target for HDAC inhibitors in treating cardiac hypertrophy and heart failure.
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