title: Estrogen regulates histone deacetylases to prevent cardiac hypertrophy.
abstract: The development and progression of cardiac hypertrophy often leads to heart failure and death, and important modulators of hypertrophy include the histone deacetylase proteins (HDACs). Estrogen inhibits cardiac hypertrophy and progression in animal models and humans. We therefore investigated the influence of 17-β-estradiol on the production, localization, and functions of prohypertrophic (class I) and antihypertrophic (class II) HDACs in cultured neonatal rat cardiomyocytes. 17-β-Estradiol or estrogen receptor β agonists dipropylnitrile and β-LGND2 comparably suppressed angiotensin II-induced HDAC2 (class I) production, HDAC-activating phosphorylation, and the resulting prohypertrophic mRNA expression. In contrast, estrogenic compounds derepressed the opposite effects of angiotensin II on the same parameters for HDAC4 and 5 (class II), resulting in retention of these deacetylases in the nucleus to inhibit hypertrophic gene expression. Key aspects were confirmed in vivo from the hearts of wild-type but not estrogen receptor β (ERβ) gene-deleted mice administered angiotensin II and estrogenic compounds. Our results identify a novel dual regulation of cardiomyocyte HDACs, shown here for the antihypertrophic sex steroid acting at ERβ. This mechanism potentially supports using ERβ agonists as HDAC modulators to treat cardiac disease.
authors.affiliation: Division of Endocrinology, Department of Medicine, University of California, Irvine, Irvine, CA 92717 Department of Veterans Affairs Medical Center, Long Beach, CA 90822 GTx, Inc., Memphis, TN 38163 Division of Cardiology, Department of Medicine, University of Colorado, Aurora, CO 80045.
authors.forename: Ali
authors.initials: A
authors.lastname: Pedram
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Razandi
authors.forename: Ramesh
authors.initials: R
authors.lastname: Narayanan
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.forename: Ellis R
authors.initials: ER
authors.lastname: Levin
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control*; D002478:Cells, Cultured; D004958:Estradiol / Q000819:agonists*; D047629:Estrogen Receptor beta / Q000819:agonists*; D004967:Estrogens / Q000819:agonists*; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics; D006321:Heart / Q000502:physiology; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006655:Histone Deacetylases / Q000096:biosynthesis; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D012097:Repressor Proteins / Q000096:biosynthesis; D015533:Transcriptional Activation
chemical_list: D047629:Estrogen Receptor beta; D004967:Estrogens; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D007546:Isoquinolines; D012333:RNA, Messenger; D012097:Repressor Proteins; C585485:beta-LGND2; D000804:Angiotensin II; D004958:Estradiol; D051745:Protein Kinase C-delta; C533423:HDAC2 protein, human; C400300:HDAC4 protein, human; C404500:HDAC5 protein, human; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases