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Nat Commun. 2017 Jan 13;8:14079. doi: 10.1038/ncomms14079.

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

Author information

1
Division of Respiratory Medicine, Department of Medicine, Box 157, Level 5, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 0QQ, UK.
2
Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge CB23 8RE, UK.
3
Department Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense. Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Calle Del Prof Martin Lagos, Madrid 28040, Spain.
4
Division of Cancer Research, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Ninewells Hospital And Medical School, Dundee DD1 9SY, UK.

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.

PMID:
28084316
PMCID:
PMC5241886
DOI:
10.1038/ncomms14079
[Indexed for MEDLINE]
Free PMC Article

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