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 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".
a Institute of Pharmacy, Nirma University, Ahmedabad 382 481, India.
Suchi
S
Raghunathan
b Delhi Pharmaceutical Sciences Research University, Delhi, India.
Ramesh K
RK
Goyal
a Institute of Pharmacy, Nirma University, Ahmedabad 382 481, India.
Bhoomika M
BM
Patel
D000818:Animals; D015415:Biomarkers / Q000097:blood; D006332:Cardiomegaly / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006439:Hemodynamics / Q000187:drug effects; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects*
D015415:Biomarkers; D004272:DNA, Mitochondrial; D056572:Histone Deacetylase Inhibitors; D008055:Lipids; D014635:Valproic Acid; C533426:Hdac2 protein, rat; C498619:Hdac5 protein, rat; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases
HDAC de classe I; HDAC de classe II; class I HDAC; class II HDAC; constriction partielle de l’aorte abdominale; magnesium valproate; partial abdominal aortic constriction (PAAC); valproate de magnésium