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Hurst, Liam A., Dunmore, Benjamin J., Long, Lu, Crosby, Alexi, Al-Lamki, Rafia, Deighton, John, Southwood, Mark, Yang, Xudong, Nikolic, Marko Z., Herrera, Blanca, Inman, Gareth J., Bradley, John R., Rana, Amer A. 
ORCID: https://orcid.org/0000-0002-2330-4643, Upton, Paul D. and Morrell, Nicholas W.
(2017)
TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling.
Nature Communications, 8 (1).
ISSN 2041-1723
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Abstract
Heterozygous germ-line mutations in the bone morphogenetic protein type-II receptor (BMPR-II) gene underlie heritable pulmonary arterial hypertension (HPAH). Although inflammation promotes PAH, the mechanisms by which inflammation and BMPR-II dysfunction conspire to cause disease remain unknown. Here we identify that tumour necrosis factor-α (TNFα) selectively reduces BMPR-II transcription and mediates post-translational BMPR-II cleavage via the sheddases, ADAM10 and ADAM17 in pulmonary artery smooth muscle cells (PASMCs). TNFα-mediated suppression of BMPR-II subverts BMP signalling, leading to BMP6-mediated PASMC proliferation via preferential activation of an ALK2/ACTR-IIA signalling axis. Furthermore, TNFα, via SRC family kinases, increases pro-proliferative NOTCH2 signalling in HPAH PASMCs with reduced BMPR-II expression. We confirm this signalling switch in rodent models of PAH and demonstrate that anti-TNFα immunotherapy reverses disease progression, restoring normal BMP/NOTCH signalling. Collectively, these findings identify mechanisms by which BMP and TNFα signalling contribute to disease, and suggest a tractable approach for therapeutic intervention in PAH.
| Item Type: | Article |
|---|---|
| Faculty \ School: | Faculty of Science > School of Biological Sciences |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 11 Nov 2020 01:15 |
| Last Modified: | 22 Oct 2022 07:26 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/77622 |
| DOI: | 10.1038/ncomms14079 |
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