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


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Abstract

Background 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 signallingin vivoin 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.SUMMARY AT A GLANCEUpregulation of BMPR2 by gene delivery in human endothelial cells and in rats with pulmonary hypertension (PAH) increases Smad1/5/8 phosphorylation, reduces Smad3 phosphorylation and induces changes in non-Smad pathways. This is the first demonstration of the effects of BMPR2 gene therapy for PAH on downstream signalling.

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