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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Selective inhibition of HDAC2 by magnesium valproate attenuates cardiac hypertrophy
Suchi Raghunathan1, Ramesh K Goyal2, Bhoomika M Patel1
1a Institute of Pharmacy, Nirma University, Ahmedabad 382 481, India.
Insights
Magnesium valproate (MgV), a potent class I histone deacetylase (HDAC) inhibitor, effectively prevented cardiac hypertrophy in rats. This study highlights selective class I HDAC inhibition as a therapeutic strategy for heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Epigenetics
Background:
- Cardiac hypertrophy involves gene expression changes regulated by chromatin remodeling.
- Histone deacetylases (HDACs), particularly class I and II, play opposing roles in hypertrophic pathways.
Purpose of the Study:
- To investigate the therapeutic potential of magnesium valproate (MgV), a selective class I HDAC inhibitor, in a rat model of cardiac hypertrophy.
- To elucidate the specific roles of HDAC subtypes in regulating cardiac hypertrophy.
Main Methods:
- Cardiac hypertrophy was induced in Wistar rats via partial abdominal aortic constriction.
- Rats were treated with MgV for 6 weeks, followed by evaluation of hypertrophic, hemodynamic, oxidative stress, and mitochondrial DNA parameters.
- HDAC mRNA expression levels were analyzed to confirm target engagement.
Main Results:
- MgV treatment significantly prevented cardiac hypertrophy, improved hemodynamic function, and reduced oxidative stress.
- Mitochondrial DNA concentration and animal survival rates were increased in the MgV-treated group.
- MgV selectively decreased pro-hypertrophic HDAC2 expression while leaving anti-hypertrophic HDAC5 expression unaltered.
Conclusions:
- Selective inhibition of class I HDACs, such as with MgV, is a promising strategy for managing cardiac hypertrophy.
- Development of novel HDAC inhibitors with dual action (class I inhibition and class II promotion) could offer enhanced therapeutic benefits.
Abstract:
The regulatory paradigm in cardiac hypertrophy involves alterations in gene expression that is mediated by chromatin remodeling. Various data suggest that class I and class II histone deacetylases (HDACs) play opposing roles in the regulation of hypertrophic pathways. To address this, we tested the effect of magnesium valproate (MgV), an HDAC inhibitor with 5 times more potency on class I HDACs. Cardiac hypertrophy was induced by partial abdominal aortic constriction in Wistar rats, and at the end of 6 weeks, we evaluated hypertrophic, hemodynamic, and oxidative stress parameters, and mitochondrial DNA concentration. Treatment with MgV prevented cardiac hypertrophy, improved hemodynamic functions, prevented oxidative stress, and increased mitochondrial DNA concentration. MgV treatment also increased the survival rate of the animals as depicted by the Kaplan-Meier curve. Improvement in hypertrophy due to HDAC inhibition was further confirmed by HDAC mRNA expression studies, which revealed that MgV decreases expression of pro-hypertrophic HDAC (i.e., HDAC2) without altering the expression of anti-hypertrophic HDAC5. Selective class I HDAC inhibition is required for controlling cardiac hypertrophy. Newer HDAC inhibitors that are class I inhibitors and class II promoters can be designed to obtain "pan" or "dual" natural HDAC "regulators".
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