Expression of mutant bone morphogenetic protein receptor II worsens pulmonary hypertension secondary to pulmonary fibrosis

• Published in: Pulmonary circulation Vol. 5; no. 4; pp. 681 - 690
• Main Authors: Bryant, Andrew J., Robinson, Linda J., Moore, Christy S., Blackwell, Thomas R., Gladson, Santhi, Penner, Niki L., Burman, Ankita, McClellan, Lucas J., Polosukhin, Vasiliy V., Tanjore, Harikrishna, McConaha, Melinda E., Gleaves, Linda A., Talati, Megha A., Hemnes, Anna R., Fessel, Joshua P., Lawson, William E., Blackwell, Timothy S., West, James D.
• Format: Journal Article
• Language: English
• Published: London, England University of Chicago Press 01-12-2015; SAGE Publications; John Wiley & Sons, Inc
• Subjects: bone morphogenetic protein receptor II (BMPR2); Bone morphogenetic proteins; Endothelial cells; Fibrosis; Genetic mutation; Hypoxia; hypoxia‐inducible factor (HIF); Idiopathic pulmonary fibrosis; idiopathic pulmonary fibrosis (IPF); Lungs; Mice; Original Research; Proteins; Pulmonary fibrosis; Pulmonary hypertension; pulmonary hypertension (PH); Reactive oxygen species; Receptors; Rodents; Transgenic animals; hypoxia-inducible factor (HIF); idiopathic pulmonary fibrosis (IPF); pulmonary hypertension (PH); bone morphogenetic protein receptor II (BMPR2)
• ISSN: 2045-8932; 2045-8940; 2045-8940
• DOI: 10.1086/683811

Pulmonary fibrosis is often complicated by pulmonary hypertension (PH), and previous studies have shown a potential link between bone morphogenetic protein receptor II (BMPR2) and PH secondary to pulmonary fibrosis. We exposed transgenic mice expressing mutant BMPR2 and control mice to repetitive intraperitoneal injections of bleomycin for 4 weeks. The duration of transgene activation was too short for mutant BMPR2 mice to develop spontaneous PH. Mutant BMPR2 mice had increased right ventricular systolic pressure compared to control mice, without differences in pulmonary fibrosis. We found increased hypoxia-inducible factor (HIF)1-α stabilization in lungs of mutant-BMPR2-expressing mice compared to controls following bleomycin treatment. In addition, expression of the hypoxia response element protein connective tissue growth factor was increased in transgenic mice as well as in a human pulmonary microvascular endothelial cell line expressing mutant BMPR2. In mouse pulmonary vascular endothelial cells, mutant BMPR2 expression resulted in increased HIF1-α and reactive oxygen species production following exposure to hypoxia, both of which were attenuated with the antioxidant TEMPOL. These data suggest that expression of mutant BMPR2 worsens secondary PH through increased HIF activity in vascular endothelium. This pathway could be therapeutically targeted in patients with PH secondary to pulmonary fibrosis.