title: Therapeutic efficacy of valproic acid in a combined monocrotaline and chronic hypoxia rat model of severe pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is a serious disease with poor prognosis. Reports show that cells in remodeled pulmonary arteries of PH patients have similar characteristics to cancer cells, such as exuberant inflammation, increased proliferation, and decreased apoptosis. An ideal strategy for developing PH therapies is to directly target pulmonary vascular remodeling. High levels of histone deacetylase (HDAC) expression and activity are found in certain cancers, and research has shown the potential of HDAC inhibitors in repressing tumor growth via anti-inflammatory and anti-proliferative effects. To date, little is known about the effectiveness of HDAC inhibitors against pulmonary vascular remodeling in severe PH.
  
  
  OBJECTIVE
  To investigate whether class I HDAC inhibitors suppress or reverse the development of severe PH in rats.
  
  
  METHODS
  Male Sprague-Dawley rats were injected with a single, subcutaneous dose of monocrotaline (60 mg/kg), and were exposed to chronic hypoxia to induce severe PH. Valproic acid, a class I HDAC inhibitor, was administered to rats daily via gastric gavage (300 mg/kg) in a PH prevention study (during the first 3 weeks) or a PH reversal study (from 3 to 5 weeks). At the end of experiment, hemodynamic indices were measured, ventricular hypertrophy indices were calculated and vascular remodeling phenotypes were analyzed.
  
  
  RESULTS
  After 3 weeks exposure to a combined stimulation of monocrotaline and chronic hypoxia, rats exhibited a reduced body weight, elevated right ventricular systolic pressure, an increased Fulton index, right ventricle weight ratio, medial wall thickness and muscularized peripheral pulmonary arteries. These parameters for PH evaluation were exacerbated from 3 to 5 weeks. Daily administration of valproic acid therapy prevented and partially reversed the development of severe PH in rats, and decreased inflammation and proliferation in remodeled pulmonary arteries.
  
  
  CONCLUSIONS
  These data show that class I HDAC inhibitors may be effective for treating severe PH.
authors: Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Beidi
authors: B
authors: Lan
authors: Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Emiko
authors: E
authors: Hayama
authors: Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Nanako
authors: N
authors: Kawaguchi
authors: Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Yoshiyuki
authors: Y
authors: Furutani
authors: Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Toshio
authors: T
authors: Nakanishi
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D000860:Hypoxia / Q000150:complications*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D016686:Monocrotaline
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