Selective inhibition of HDAC2 by magnesium valproate attenuates cardiac hypertrophy

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 HDAC. Cardiac hypertrophy was induced by Partial abdominal aortic constriction in wistar rats, and at 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 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 which are class I inhibitor and class II promoter can be designed to obtain a ‘pan’ or ‘dual’ natural HDAC ‘regulators.