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Type: Journal article
Title: BMPR2 gene delivery reduces mutation-related PAH and counteracts TGF-β-mediated pulmonary cell signalling
Other Titles: BMPR2 gene delivery reduces mutation-related PAH and counteracts TGF-beta-mediated pulmonary cell signalling
Author: Feng, F.
Harper, R.
Reynolds, P.
Citation: Respirology, 2016; 21(3):526-532
Publisher: Wiley
Issue Date: 2016
ISSN: 1323-7799
Statement of
Feng Feng, Rebecca L Harper and Paul N Reynolds
Abstract: Background and objective: Idiopathic, familial and secondary pulmonary arterial hypertension (PAH) are associated with reduced bone morphogenetic protein receptor type 2 (BMPR2) expression, and in some contexts, TGF-β upregulation. Our aims were to assess BMPR2 gene therapy in a PAH mouse model and to assess the impact on TGF-β signalling. Methods: Using a targeted in vivo gene delivery approach, we assessed the impact of BMPR2 gene delivery in a transgenic mouse model in which PAH was first induced by doxycycline driven expression of a dominant negative BMPR2 mutant (R899X). We also assessed the impact of BMPR2 gene delivery on TGF-β-induced changes in cell signalling in human pulmonary vascular endothelial and smooth muscle cells. Results: In the mouse model, changes in TGF-β levels were not detected, but BMPR2 gene delivery reversed the increase in right ventricle systolic pressure (RVSP) and Fulton Index (FI), associated with a trend to increased pulmonary endothelial nitric oxide synthase (eNOS) gene expression. In vitro, BMPR2 gene transfer reduced TGF-β effects on Smad2, Smad1/5/8 and Erk1/2 phosphorylation in human pulmonary arterial smooth muscle cells (HPASMC). BMPR2 was also found to upregulate nitric oxide (NO) production in lung derived human microvascular endothelial cells (HMVEC-L). Conclusion: This study provides further evidence that BMPR2 modulation may have therapeutic potential.
Keywords: Genetics; molecular biology; nitric oxide; pulmonary circulation and pulmonary hypertension
Rights: © 2015 Asian Pacific Society of Respirology
DOI: 10.1111/resp.12712
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