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A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy
Tetsuro Ago1, Tong Liu, Peiyong Zhai
1Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA.
Cell
|June 17, 2008
Summary
Thioredoxin 1 (Trx1) reduces oxidative stress in cardiac hypertrophy by modifying histone deacetylases (HDACs). This redox regulation prevents HDAC nuclear export, offering a novel therapeutic target for heart disease.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Redox Biology
Background:
- Thioredoxin 1 (Trx1) is a key regulator of cellular redox balance, influencing cell growth and death.
- Cardiac hypertrophy, an increase in heart muscle mass, is a maladaptive response often leading to heart failure.
- Class II histone deacetylases (HDACs) are critical negative regulators of cardiac hypertrophy.
Purpose of the Study:
- To elucidate the molecular mechanism by which Trx1 attenuates cardiac hypertrophy.
- To investigate the role of redox modification in the regulation of class II HDACs during cardiac hypertrophy.
Main Methods:
- Investigated Trx1-mediated regulation of DnaJb5 and class II HDACs.
- Analyzed the redox modification (oxidation and reduction) of specific cysteine residues in DnaJb5 and HDAC4.
- Assessed the impact of these modifications on protein-protein interactions and subcellular localization (nuclear export).
Main Results:
- Trx1 upregulates DnaJb5 and forms a complex with DnaJb5 and class II HDACs.
- Trx1 reduces oxidized cysteine residues in DnaJb5 (Cys-274/Cys-276) and HDAC4 (Cys-667/Cys-669) under hypertrophic stimuli.
- Reduction of DnaJb5 cysteines is crucial for DnaJb5-HDAC4 interaction, while reduction of HDAC4 cysteines inhibits its nuclear export.
Conclusions:
- Cardiac hypertrophy is regulated by a novel Trx1-sensitive mechanism involving redox modification of class II HDACs.
- Redox modification of HDAC4 by Trx1 modulates its nucleocytoplasmic shuttling, impacting hypertrophic signaling.
- This study reveals a potential therapeutic strategy targeting redox pathways in cardiac hypertrophy.
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