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Research ArticleArticle

Histone Deacetylase Inhibition Attenuates Cardiac Hypertrophy and Fibrosis through Acetylation of Mineralocorticoid Receptor in Spontaneously Hypertensive Rats

Seol-Hee Kang, Young Mi Seok, Min-ji Song, Hae-Ahm Lee, Thomas Kurz and InKyeom Kim
Molecular Pharmacology May 2015, 87 (5) 782-791; DOI: https://doi.org/10.1124/mol.114.096974
Seol-Hee Kang
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.)
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Young Mi Seok
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.)
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Min-ji Song
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.)
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Hae-Ahm Lee
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.)
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Thomas Kurz
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.)
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InKyeom Kim
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.)
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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.

Footnotes

    • Received November 19, 2014.
    • Accepted February 9, 2015.
  • Seol-Hee Kang and Young Mi Seok contributed equally to this work.

  • This research was supported by Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology [2013R1A2A2A01005155, 2013K2A4A1044932 and 2013K2A1B9061222, 2014K2A5A3000021, 2014K2A4A1034762 and 2014K1A3A1A09063332], and the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [HI13C1527].

  • dx.doi.org/10.1124/mol.114.096974.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (5)
Molecular Pharmacology
Vol. 87, Issue 5
1 May 2015
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Research ArticleArticle

HDAC Inhibition Attenuates Cardiac Hypertrophy

Seol-Hee Kang, Young Mi Seok, Min-ji Song, Hae-Ahm Lee, Thomas Kurz and InKyeom Kim
Molecular Pharmacology May 1, 2015, 87 (5) 782-791; DOI: https://doi.org/10.1124/mol.114.096974

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Research ArticleArticle

HDAC Inhibition Attenuates Cardiac Hypertrophy

Seol-Hee Kang, Young Mi Seok, Min-ji Song, Hae-Ahm Lee, Thomas Kurz and InKyeom Kim
Molecular Pharmacology May 1, 2015, 87 (5) 782-791; DOI: https://doi.org/10.1124/mol.114.096974
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