| Autor: |
Ogo T; Department of Medical and Molecular Genetics, School of Medicine, King's College London, London, United Kingdom., Chowdhury HM, Yang J, Long L, Li X, Torres Cleuren YN, Morrell NW, Schermuly RT, Trembath RC, Nasim MT |
| Jazyk: |
angličtina |
| Zdroj: |
American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2013 Jun; Vol. 48 (6), pp. 733-41. |
| DOI: |
10.1165/rcmb.2012-0049OC |
| Abstrakt: |
The 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, underlies 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 effects of currently used therapies on the TGF-β pathway remain unknown. Prostacyclin analogs comprise 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 analog, selectively inhibits proliferation in a dose-dependent manner in murine primary pulmonary arterial smooth muscle cells (PASMCs) harboring a pathogenic BMPR2 nonsense mutation in both the presence and absence of TGF-β1 stimulation. Our study demonstrates that this agent inhibits TGF-β1-induced SMAD-dependent and SMAD-independent signaling via a protein kinase A-dependent pathway by reducing the phosphorylation of SMADs 2 and 3 and p38 mitogen-activated protein kinase proteins. Finally, in a monocrotaline-induced rat model of PAH, which is associated with increased TGF-β signaling, this study confirms that treprostinil, a stable prostacyclin analog, inhibits the TGF-β pathway by reducing SMAD3 phosphorylation. Taken together, these data suggest that prostacyclin analogs inhibit dysregulated TGF-β signaling in vitro and in vivo, and reduce BMPR-II-mediated proliferation defects in mutant mice PASMCs. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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