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dc.contributor.authorNasim, Md. Talat*
dc.contributor.authorOgo, T.*
dc.contributor.authorChowdhury, H.M.*
dc.contributor.authorZhao, L.*
dc.contributor.authorChen, C-n.*
dc.contributor.authorRhodes, C.*
dc.contributor.authorTrembath, R.C.*
dc.date.accessioned2014-04-28T11:05:01Z
dc.date.available2014-04-28T11:05:01Z
dc.date.issued2012
dc.identifier.citationNasim MT, Ogo T, Chowdhury HM, Zhao L, Chen C, Rhodes C and Trembath RC (2012) BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFbeta-TAK1-MAPK pathways in PAH. Human Molecular Genetics. 21(11): 2548-2558.
dc.identifier.urihttp://hdl.handle.net/10454/6115
dc.descriptionYes
dc.description.abstractPulmonary arterial hypertension (PAH) is a cardiovascular disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR2) underlie the majority of the inherited and familial forms of PAH. The transforming growth factor beta (TGFbeta) pathway is activated in both human and experimental models of PAH. However, how these factors exert pro-proliferative and anti-apoptotic responses in PAH remains unclear. Using mouse primary PASMCs derived from knock-in mice, we demonstrated that BMPR-II dysfunction promotes the activation of small mothers against decapentaplegia-independent mitogen-activated protein kinase (MAPK) pathways via TGFbeta-associated kinase 1 (TAK1), resulting in a pro-proliferative and anti-apoptotic response. Inhibition of the TAK1-MAPK axis rescues abnormal proliferation and apoptosis in these cells. In both hypoxia and monocrotaline-induced PAH rat models, which display reduced levels of bmpr2 transcripts, this study further indicates that the TGFbeta-MAPK axis is activated in lungs following elevation of both expression and phosphorylation of the TAK1 protein. In ex vivo cell-based assays, TAK1 inhibits BMP-responsive reporter activity and interacts with BMPR-II receptor. In the presence of pathogenic BMPR2 mutations observed in PAH patients, this interaction is greatly reduced. Taken together, these data suggest dysfunctional BMPR-II responsiveness intensifies TGFbeta-TAK1-MAPK signalling and thus alters the ratio of apoptosis to proliferation. This axis may be a potential therapeutic target in PAH.
dc.language.isoen
dc.subjectAnimals
dc.subject
dc.subjectApoptosis
dc.subject
dc.subjectBone morphogenetic protein receptors
dc.subjectType II
dc.subjectMetabolism
dc.subject
dc.subjectCell proliferation
dc.subject
dc.subjectCells
dc.subjectCultured
dc.subject
dc.subjectHypertension
dc.subjectPulmonary
dc.subjectPathology
dc.subject
dc.subjectMAP kinase
dc.subject
dc.subjectMice
dc.subject
dc.subjectPulmonary artery
dc.subject
dc.subjectRats
dc.subject
dc.subjectSignal transduction
dc.subject
dc.subjectTransforming growth factor beta
dc.subject
dc.subjectREF 2014
dc.titleBMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFbeta-TAK1-MAPK pathways in PAH
dc.typeArticle
dc.type.versionAccepted manuscript
dc.identifier.doihttps://doi.org/10.1093/hmg/dds073
dc.rights.licenseUnspecified
refterms.dateFOA2018-07-19T10:21:58Z
dc.openaccess.statusopenAccess


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