title: Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy.
abstract: BACKGROUND
  Recent work has demonstrated the importance of chromatin remodeling, especially histone acetylation, in the control of gene expression in the heart. In cell culture models of cardiac hypertrophy, pharmacological suppression of histone deacetylases (HDACs) can either blunt or amplify cell growth. Thus, HDAC inhibitors hold promise as potential therapeutic agents in hypertrophic heart disease.
  
  
  RESULTS
  In the present investigation, we studied 2 broad-spectrum HDAC inhibitors in a physiologically relevant banding model of hypertrophy, observing dose-responsive suppression of ventricular growth that was well tolerated in terms of both clinical outcome and cardiac performance measures. In both short-term (3-week) and long-term (9-week) trials, cardiomyocyte growth was blocked by HDAC inhibition, with no evidence of cell death or apoptosis. Fibrotic change was diminished in hearts treated with HDAC inhibitors, and collagen synthesis in isolated cardiac fibroblasts was blocked. Preservation of systolic function in the setting of blunted hypertrophic growth was documented by echocardiography and by invasive pressure measurements. The hypertrophy-associated switch of adult and fetal isoforms of myosin heavy chain expression was attenuated, which likely contributed to the observed preservation of systolic function in HDAC inhibitor-treated hearts.
  
  
  CONCLUSIONS
  Together, these data suggest that HDAC inhibition is a viable therapeutic strategy that holds promise in the treatment of load-induced heart disease.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Kong
authors.forename: Paul
authors.initials: P
authors.lastname: Tannous
authors.forename: Guangrong
authors.initials: G
authors.lastname: Lu
authors.forename: Kambeez
authors.initials: K
authors.lastname: Berenji
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D006898:Hydroxylamines / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D018995:Myosin Heavy Chains / Q000032:analysis / Q000235:genetics; D045265:Natriuretic Peptides / Q000032:analysis / Q000235:genetics; D020033:Protein Isoforms; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D013997:Time Factors; D014463:Ultrasonography; D016276:Ventricular Function / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D006898:Hydroxylamines; D045265:Natriuretic Peptides; D020033:Protein Isoforms; D011804:Quinolines; D012097:Repressor Proteins; C410733:scriptaid; C012589:trichostatin A; C110550:HDAC1 protein, human; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D018995:Myosin Heavy Chains