期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms14079
关键词
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资金
- British Heart Foundation [RG/13/4/30107, CH/09/001/25945]
- Medical Research Council Experimental Challenge Award
- Fondation Leducq Transatlantic Network of Excellence
- Dinosaur Trust
- UK National Institute for Health Research Healthcare Science Fellowship
- BHF PhD student programme [FS/09/050]
- British Heart Foundation [PG/13/91/30579, RG/13/4/30107, PG/14/31/30786, SP/12/12/29836] Funding Source: researchfish
- Medical Research Council [MR/K020919/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10014, NF-SI-0514-10086] Funding Source: researchfish
- MRC [MR/K020919/1] Funding Source: UKRI
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-alpha (TNF alpha) selectively reduces BMPR-II transcription and mediates posttranslational BMPR-II cleavage via the sheddases, ADAM10 and ADAM17 in pulmonary artery smooth muscle cells (PASMCs). TNF alpha-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, TNF alpha, 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-TNF alpha immunotherapy reverses disease progression, restoring normal BMP/NOTCH signalling. Collectively, these findings identify mechanisms by which BMP and TNF alpha signalling contribute to disease, and suggest a tractable approach for therapeutic intervention in PAH.
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