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dc.contributor.authorHurst, LAen
dc.contributor.authorDunmore, Benjaminen
dc.contributor.authorLong, Luen
dc.contributor.authorCrosby, Aen
dc.contributor.authorAl-Lamki, Rafiaen
dc.contributor.authorDeighton, Jen
dc.contributor.authorSouthwood, Men
dc.contributor.authorYang, XuDongen
dc.contributor.authorNikolic, Markoen
dc.contributor.authorHerrera, Ben
dc.contributor.authorInman, GJen
dc.contributor.authorBradley, Johnen
dc.contributor.authorRana, Mooen
dc.contributor.authorUpton, Paulen
dc.contributor.authorMorrell, Nicholasen
dc.date.accessioned2017-02-20T13:01:01Z
dc.date.available2017-02-20T13:01:01Z
dc.date.issued2017-01-13en
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/262664
dc.description.abstractHeterozygous 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.
dc.description.sponsorshipThis 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.
dc.languageengen
dc.language.isoenen
dc.publisherNature Publishing Group
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleTNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signallingen
dc.typeArticle
prism.number14079en
prism.publicationDate2017en
prism.publicationNameNature Communicationsen
prism.volume8en
dc.identifier.doi10.17863/CAM.7934
dcterms.dateAccepted2017-01-03en
rioxxterms.versionofrecord10.1038/ncomms14079en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-01-13en
dc.contributor.orcidNikolic, Marko [0000-0001-6304-6848]
dc.contributor.orcidBradley, John [0000-0002-7774-8805]
dc.contributor.orcidRana, Moo [0000-0002-2330-4643]
dc.contributor.orcidUpton, Paul [0000-0003-2716-4921]
dc.contributor.orcidMorrell, Nicholas [0000-0001-5700-9792]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MR/K020919/1)
pubs.funder-project-idBritish Heart Foundation (RG/13/4/30107)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idDinosaur Trust (unknown)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idBritish Heart Foundation (PG/14/31/30786)
pubs.funder-project-idBritish Heart Foundation (CH/09/001/25945)
pubs.funder-project-idBritish Heart Foundation (PG/13/91/30579)
pubs.funder-project-idBritish Heart Foundation (SP/12/12/29836)
cam.issuedOnline2017-01-13en
cam.orpheus.successThu Jan 30 12:56:40 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International