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dc.contributor.authorOgo, T.
dc.contributor.authorChowdhury, H.M.
dc.contributor.authorYang, J.
dc.contributor.authorLong, T.
dc.contributor.authorLi, X.
dc.contributor.authorTorres Cleuven, Y.N.
dc.contributor.authorMorrell, N.W.
dc.contributor.authorSchermuly, R.T.
dc.contributor.authorTrembath, R.C.
dc.contributor.authorNasim, Md. Talat
dc.date.accessioned2016-03-21T14:30:34Z
dc.date.available2016-03-21T14:30:34Z
dc.date.issued2013-06
dc.identifier.citationOgo T, Chowdhury HM, Yang J, et al (2013) Inhibition of Overactive Transforming Growth Factor–β Signaling by Prostacyclin Analogs in Pulmonary Arterial Hypertension. American Journal of Respiratory Cell and Molecular Biology. 48(6): 733-741.en_US
dc.identifier.urihttp://hdl.handle.net/10454/7969
dc.descriptionYesen_US
dc.description.abstractHeterozygous loss of function mutations in the type II bone morphogenetic protein receptor (BMPR-II), a member of the transforming growth factor (TGF-β) receptor family, underlie the majority of familial cases of pulmonary arterial hypertension (PAH). The TGF-β1 pathway is activated in PAH and inhibitors of TGF-β1 signaling prevent the development and progression of PAH in experimental models. However, the effect of currently utilized therapies on the TGF-β pathway is not known. Prostacyclin analogues remain the first line of treatment for clinical PAH. We hypothesized that these agents effectively decrease the activity of the TGF-β1 pathway. Beraprost sodium (BPS), a prostacyclin analogue selectively inhibits proliferation in a dose-dependent manner in mouse primary pulmonary arterial smooth muscle cells (PASMCs) harbouring a pathogenic BMPR2 nonsense mutation in both the presence and absence of TGF-β1 stimulation. This study demonstrates that this agent inhibits TGF-β1–induced SMAD-dependent and -independent signaling via a PKA dependent pathway by reducing the phosphorylation of SMADs 2 and 3 and p38MAPK proteins. Finally, in a monocrotaline (MCT)-induced rat model of PAH, which is associated with increased TGF-β signaling, this study confirms that treprostinil (TPS), a stable prostacyclin analogue, inhibits the TGF-β pathway by reducing SMAD3 phosphorylation. Taken together, these data suggest that prostacyclin analogues inhibit dysregulated TGF-β signaling in vitro and in vivo and reduce BMPR-II-mediated proliferation defects in mutant mice PASMCs.en_US
dc.description.sponsorshipThe authors acknowledge financial support from the British Heart Foundation, United Kingdom (Programme Grant 1-2004-357 to R.C.T. and N.W.M.), a Heptagon Life Science Proof of Concept Fund (grants KCL24 and KCL25 to M.T.N. and R.C.T., respectively), and the Great Britain Sasakawa Foundation (grant B70 to M.T.N.)en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttp://dx.doi.org/10.1165/rcmb.2012-0049OCen_US
dc.rights© 2013 The American Thoracic Society. Full-text reproduced in accordance with the publisher’s self-archiving policy.en_US
dc.subjectPAH; BMPR2; TGF-β signalling; Prostacyclins; PASMCen_US
dc.titleInhibition of Overactive Transforming Growth Factor–β Signaling by Prostacyclin Analogs in Pulmonary Arterial Hypertensionen_US
dc.status.refereedYesen_US
dc.date.Accepted2012-10-19
dc.typeArticleen_US
dc.type.versionAccepted Manuscripten_US
refterms.dateFOA2018-07-25T14:20:10Z


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