PT  - JOURNAL ARTICLE
AU  - Seol hee Kang
AU  - Young mi Seok
AU  - Min ji Song
AU  - Hae ahm Lee
AU  - Thomas Kurz
AU  - Inkyeom Kim
TI  - Histone Deacetylase Inhibition Attenuates Cardiac Hypertrophy and Fibrosis through Acetylation of Mineralocorticoid Receptor in Spontaneously Hypertensive Rats
AID  - 10.1124/mol.114.096974
DP  - 2015 Feb 09
TA  - Molecular Pharmacology
PG  - mol.114.096974
4099  - http://molpharm.aspetjournals.org/content/early/2015/02/09/mol.114.096974.short
4100  - http://molpharm.aspetjournals.org/content/early/2015/02/09/mol.114.096974.full
AB  - Inhibition of histone deacetylases (HDACs) by valproic acid (VPA) attenuates inflammatory, hypertrophic, and fibrotic responses in the hearts of spontaneously hypertensive rats (SHRs). However, the molecular mechanism is still unclear. We hypothesized that HDAC inhibition (HDACi) attenuates cardiac hypertrophy and fibrosis through acetylation of mineralocorticoid receptor (MR) in SHRs. Seven-week-old SHRs and Wistar-Kyoto rats (WKYs) were treated with an HDAC class I inhibitor (0.71% w/v in drinking water; VPA) for 11 weeks. Sections of heart were visualized after trichrome stain as well as hematoxylin and eosin stain. Histone modifications, such as acetylation (H3Ac) and fourth lysine trimethylation (H3K4me3) of histone 3, and recruitment of MR and RNA polymerase II (Pol II) into promoters of target genes were measured by quantitative real-time PCR (qRT-PCR) after chromatin immunoprecipitation (ChIP) assay. MR acetylation was determined by western blot with anti-acetyl-lysine antibody after immunoprecipitation (IP) with anti-MR antibody. Treatment with VPA attenuated cardiac hypertrophy and fibrosis. Although treatment with VPA increased H3Ac and H3K4me3 on promoter regions of MR target genes, expression of MR target genes as well as recruitment of MR and Pol II on promoters of target genes were decreased. Although HDACi did not affect MR expression, it increased MR acetylation. These results indicate that HDACi attenuates cardiac hypertrophy and fibrosis through acetylation of MR in spontaneously hypertensive rats.