BMPR2 gene therapy for PAH acts via Smad and non-Smad signalling

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dc.contributor.authorHarper, R.
dc.contributor.authorReynolds, A.
dc.contributor.authorBonder, C.
dc.contributor.authorReynolds, P.
dc.date.issued2016
dc.description.abstractBackground and 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). Conclusion: 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.
dc.description.statementofresponsibilityRebecca L. Harper, Ann M. Reynolds, Claudine S. Bonder and Paul N. Reynolds
dc.identifier.citationRespirology, 2016; 21(4):727-733
dc.identifier.doi10.1111/resp.12729
dc.identifier.issn1323-7799
dc.identifier.issn1440-1843
dc.identifier.orcidHarper, R. [0000-0003-1465-7372]
dc.identifier.orcidBonder, C. [0000-0001-9875-967X]
dc.identifier.orcidReynolds, P. [0000-0002-2273-1774]
dc.identifier.urihttp://hdl.handle.net/2440/106993
dc.language.isoen
dc.publisherWiley-Blackwell
dc.relation.grantNHMRC
dc.rights© 2016 Asian Pacific Society of Respirology
dc.source.urihttps://doi.org/10.1111/resp.12729
dc.subjectAdenovirus; bone morphogenetic receptor type 2; endothelium; gene therapy; pulmonary hypertension
dc.titleBMPR2 gene therapy for PAH acts via Smad and non-Smad signalling
dc.typeJournal article
pubs.publication-statusPublished

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