Selective inhibition of HDAC2 by magnesium valproate attenuates cardiac hypertrophy

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'.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Systemic study of selected HDAC inhibitors in cardiac complications associated with cancer cachexia

Cancer cachexia is mainly characterized by wasting of skeletal muscles, fat and body weight loss, along with severe complications of major organs like liver, heart, brain and bone. There can be diminishing performance of these major organs as cancer cachexia progresses, one such drastic effect on the cardiac system. In present study, differential effect of histone deacetylase inhibitors (HDACi) on cardiac complications associated with cancer cachexia is studied. Two models were used to induce cancer cachexia: B16F1 induced metastatic cancer cachexia and LLC induced cancer cachexia. Potential of Class I HDAC inhibitor Entinostat, Class II HDAC inhibitor MC1568 and non-specific HDAC inhibitor sodium butyrate on cardiac complications were evaluated using the cardiac hypertrophy markers, hemodynamic markers and cardiac markers along with histopathological evaluation of heart sections by periodic acid schiff staining, masson trichrome staining, picro sirius red staining and haematoxylin and eosin staining. Immunohistochemistry evaluation by vimentin and caspase 3 protein expression was evaluated. Entinostat showed promising results by attenuating the cardiac complications, MC1568 treatment further exacerbated the cardiac complications while non-conclusive effect were recorded after treatment with sodium butyrate. Further, this study will be helpful in evaluating other HDAC inhibitors for potential in cardiac complications associated with cancer cachexia.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author