title: BMPR2 gene therapy for PAH acts via Smad and non-Smad signalling.
abstract: OBJECTIVE
  Pulmonary arterial hypertension (PAH) continues to be a fatal disease and is associated with downregulation of bone morphogenetic protein receptor type-2 (BMPR2). Our approach is to upregulate BMPR2 in the pulmonary vasculature allowing us to examine the changes in endothelial cell signalling and better understand what pathways are altered when disease is attenuated using this treatment approach.
  
  
  METHODS
  We used gene delivery of BMPR2 to human pulmonary endothelial cells to investigate downstream signalling, then assessed the impact of this approach on downstream signalling in vivo in rats with PAH using the monocrotaline (MCT) model.
  
  
  RESULTS
  Gene delivery of BMPR2 leads to an increase in BMPR2 protein expression, and this is associated with increased Smad1/5/8 and reduced Smad2/3 signalling. Additionally, we have found that BMPR2 modulation has effects on non-Smad signalling with increases found in phosphoinositide-3 kinase (PI3K) and a decrease in phosphorylated-p38-mitogen activated protein kinase (p38-MAPK) in vivo. These findings are associated with amelioration of PAH (reduced right ventricular, mean pulmonary artery pressures and Fulton Index).
  
  
  CONCLUSIONS
  These results indicate that the therapeutic effect of BMPR2 gene delivery on PAH is associated with a switch between TGF-β-Smad2/3 signalling to BMPR2-Smad1/5/8 signalling. This supports the further development of this treatment approach.
authors.affiliation: Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia.|Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Harper
authors.affiliation: Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Reynolds
authors.affiliation: Vascular Biology Laboratory, Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Claudine S
authors.initials: CS
authors.lastname: Bonder
authors.affiliation: Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia.|Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.|Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000627:therapeutic use; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011651:Pulmonary Artery / Q000503:physiopathology*; D051381:Rats; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051896:Smad Proteins, Receptor-Regulated; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: adenovirus; bone morphogenetic receptor type 2; endothelium; gene therapy; pulmonary hypertension