Loading...
Inhibition of Overactive Transforming Growth Factor–β Signaling by Prostacyclin Analogs in Pulmonary Arterial Hypertension
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
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
Publication Date
2013-06
End of Embargo
Supervisor
Keywords
Rights
© 2013 The American Thoracic Society. Full-text reproduced in accordance with the publisher's self-archiving policy.
Peer-Reviewed
Yes
Open Access status
openAccess
Accepted for publication
2012-10-19
Institution
Department
Awarded
Embargo end date
Collections
Abstract
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.
Version
Accepted manuscript
Citation
Ogo 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.
Link to publisher’s version
Link to published version
Link to Version of Record
Type
Article