title: Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism.
abstract: BACKGROUND
  Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension with associated right ventricular cardiac remodeling are poorly understood.
  
  
  OBJECTIVE
  This study was performed to assess the utility of selective small-molecule inhibitors of class I HDACs in a preclinical model of pulmonary hypertension.
  
  
  RESULTS
  Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compound reduced pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathological gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression.
  
  
  CONCLUSIONS
  By targeting distinct pathogenic mechanisms, isoform-selective HDAC inhibitors have potential as novel therapeutics for pulmonary hypertension that will complement vasodilator standards of care.
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Cavasin
authors.forename: Kim
authors.initials: K
authors.lastname: Demos-Davies
authors.forename: Todd R
authors.initials: TR
authors.lastname: Horn
authors.forename: Lori A
authors.initials: LA
authors.lastname: Walker
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Lemon
authors.forename: Nicholas
authors.initials: N
authors.lastname: Birdsey
authors.forename: Mary C M
authors.initials: MC
authors.lastname: Weiser-Evans
authors.forename: Julie
authors.initials: J
authors.lastname: Harral
authors.forename: David C
authors.initials: DC
authors.lastname: Irwin
authors.forename: Adil
authors.initials: A
authors.lastname: Anwar
authors.forename: Michael E
authors.initials: ME
authors.lastname: Yeager
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Peter A
authors.initials: PA
authors.lastname: Watson
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
authors.forename: Peter M
authors.initials: PM
authors.lastname: Buttrick
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C118739:entinostat; C523184:mocetinostat; D006655:Histone Deacetylases