Repository logo
 

TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling

Published version
Peer-reviewed

Change log

Authors

Hurst, LA 
Dunmore, BJ 
Long, L 
Crosby, A 
Al-Lamki, R 

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.

Description

Keywords

ADAM10 Protein, Animals, Bone Morphogenetic Protein 6, Bone Morphogenetic Protein Receptors, Type II, Familial Primary Pulmonary Hypertension, Female, Humans, Male, Mice, Mice, Inbred C57BL, Myocytes, Smooth Muscle, Pulmonary Artery, Rats, Receptor, Notch2, Receptor, Notch3, Signal Transduction, Tumor Necrosis Factor-alpha

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

8

Publisher

Nature Publishing Group
Sponsorship
Medical Research Council (MR/K020919/1)
British Heart Foundation (None)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Dinosaur Trust (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
This work was supported by grants from the British Heart Foundation, RG/13/4/30107 (N.W.M.), CH/09/001/25945 (N.W.M.), a Medical Research Council Experimental Challenge Award (N.W.M.), a Fondation Leducq Transatlantic Network of Excellence (N.W.M.), the Dinosaur Trust (A.R.) and a UK National Institute for Health Research Healthcare Science Fellowship (M.S.). L.A.H. was funded through a BHF PhD student programme (FS/09/050). The UK National Institute for Health Research Cambridge Biomedical Research Centre and Cell Phenotyping Hub provided infrastructure support.