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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.

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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.
Department of Pathology, Papworth Hospital, Papworth Everard, Cambridge CB23 8RE, UK.
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.
Division of Cancer Research, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Ninewells Hospital And Medical School, Dundee DD1 9SY, UK.


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.

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