title: Role of the TGF-beta/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension is a progressive disease characterized by an elevation in the mean pulmonary artery pressure leading to right heart failure and a significant risk of death. Alterations in two transforming growth factor (TGF) signaling pathways, bone morphogenetic protein receptor II and the TGF-beta receptor I, Alk1, have been implicated in the pathogenesis of pulmonary hypertension (PH). However, the role of TGF-beta family signaling in PH and pulmonary vascular remodeling remains unclear.
  
  
  OBJECTIVE
  To determine whether inhibition of TGF-beta signaling will attenuate and reverse monocrotaline-induced PH (MCT-PH).
  
  
  METHODS
  We have used an orally active small-molecule TGF-beta receptor I inhibitor, SD-208, to determine the functional role of this pathway in MCT-PH.
  
  
  RESULTS
  The development of MCT-PH was associated with increased vascular cell apoptosis, which paralleled TGF-beta signaling as documented by psmad2 expression. Inhibition of TGF-beta signaling with SD-208 significantly attenuated the development of the PH and reduced pulmonary vascular remodeling. These effects were associated with decreased early vascular cell apoptosis, adventitial cell proliferation, and matrix metalloproteinase expression. Inhibition of TGF-beta signaling with SD-208 in established MCT-PH resulted in a small but significant improvement in hemodynamic parameters and medial remodeling.
  
  
  CONCLUSIONS
  These findings provide evidence that increased TGF-beta signaling participates in the pathogenesis of experimental severe PH.
authors.affiliation: Johns Hopkins School of Medicine, Division of Pulmonary and Critical Care Medicine, 1830 East Monument Street, 5th Floor, Baltimore, MD 21205, USA. azaiman1@jhmi.edu
authors.forename: Ari L
authors.initials: AL
authors.lastname: Zaiman
authors.forename: Megan
authors.initials: M
authors.lastname: Podowski
authors.forename: Satya
authors.initials: S
authors.lastname: Medicherla
authors.forename: Kimberley
authors.initials: K
authors.lastname: Gordy
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhen
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Shimoda
authors.forename: Enid
authors.initials: E
authors.lastname: Neptune
authors.forename: Linda
authors.initials: L
authors.lastname: Higgins
authors.forename: Alison
authors.initials: A
authors.lastname: Murphy
authors.forename: Sarvajit
authors.initials: S
authors.lastname: Chakravarty
authors.forename: Andrew
authors.initials: A
authors.lastname: Protter
authors.forename: Pravin B
authors.initials: PB
authors.lastname: Sehgal
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells; D022781:Hepatocytes; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D016686:Monocrotaline / Q000008:administration & dosage / Q000633:toxicity; D010936:Plant Extracts / Q000008:administration & dosage / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D010936:Plant Extracts; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D016686:Monocrotaline; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat