Yes / Heterozygous 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. / The 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.)
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/7969 |
| Date | 19 October 2012 |
| Creators | Ogo, T., Chowdhury, H.M., Yang, J., Long, T., Li, X., Torres Cleuven, Y.N., Morrell, N.W., Schermuly, R.T., Trembath, R.C., Nasim, Md. Talat |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Article, Accepted Manuscript |
| Rights | © 2013 The American Thoracic Society. Full-text reproduced in accordance with the publisher’s self-archiving policy. |
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