title: Histone deacetylase inhibition attenuates cardiac hypertrophy and fibrosis through acetylation of mineralocorticoid receptor in spontaneously hypertensive rats.
abstract: 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 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 H&E stain. Histone modifications, such as acetylation (H3Ac [acetylated histone 3]) 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 polymerase chain reaction after chromatin immunoprecipitation assay. MR acetylation was determined by Western blot with anti-acetyl-lysine antibody after immunoprecipitation 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.
authors: Department of Pharmacology (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Cardiovascular Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Cell and Matrix Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Brain Korea 21 Plus Kyungpook National University Biomedical Convergence Program (S.-H.K., I.K.), Department of Biomedical Science, Kyungpook National University School of Medicine (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Daegu, Republic of Korea; and Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany (T.K.).
authors: Seol-Hee
authors: SH
authors: Kang
authors: Department of Pharmacology (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Cardiovascular Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Cell and Matrix Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Brain Korea 21 Plus Kyungpook National University Biomedical Convergence Program (S.-H.K., I.K.), Department of Biomedical Science, Kyungpook National University School of Medicine (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Daegu, Republic of Korea; and Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany (T.K.).
authors: Young Mi
authors: YM
authors: Seok
authors: Department of Pharmacology (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Cardiovascular Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Cell and Matrix Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Brain Korea 21 Plus Kyungpook National University Biomedical Convergence Program (S.-H.K., I.K.), Department of Biomedical Science, Kyungpook National University School of Medicine (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Daegu, Republic of Korea; and Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany (T.K.).
authors: Min-ji
authors: MJ
authors: Song
authors: Department of Pharmacology (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Cardiovascular Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Cell and Matrix Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Brain Korea 21 Plus Kyungpook National University Biomedical Convergence Program (S.-H.K., I.K.), Department of Biomedical Science, Kyungpook National University School of Medicine (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Daegu, Republic of Korea; and Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany (T.K.).
authors: Hae-Ahm
authors: HA
authors: Lee
authors: Department of Pharmacology (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Cardiovascular Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Cell and Matrix Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Brain Korea 21 Plus Kyungpook National University Biomedical Convergence Program (S.-H.K., I.K.), Department of Biomedical Science, Kyungpook National University School of Medicine (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Daegu, Republic of Korea; and Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany (T.K.).
authors: Thomas
authors: T
authors: Kurz
authors: Department of Pharmacology (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Cardiovascular Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Cell and Matrix Research Institute (S.-H.K., Y.M.S., H.-A.L., I.K.), Brain Korea 21 Plus Kyungpook National University Biomedical Convergence Program (S.-H.K., I.K.), Department of Biomedical Science, Kyungpook National University School of Medicine (S.-H.K., Y.M.S., M.S., H.-A.L., I.K.), Daegu, Republic of Korea; and Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany (T.K.) inkim@knu.ac.kr.
authors: InKyeom
authors: I
authors: Kim
mesh_terms: D000107:Acetylation / Q000187:drug effects*; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation / Q000379:methods; D005355:Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D018161:Receptors, Mineralocorticoid; D012319:RNA Polymerase II; D006655:Histone Deacetylases