Document Detail

Inhibition of overactive transforming growth factor-β signaling by prostacyclin analogs in pulmonary arterial hypertension.
MedLine Citation:
PMID:  23418342     Owner:  NLM     Status:  MEDLINE    
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.
Takeshi Ogo; H M Chowdhury; Jun Yang; Lu Long; Xiaohui Li; Yamila N Torres Cleuren; Nicholas W Morrell; Ralph T Schermuly; Richard C Trembath; Md Talat Nasim
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  48     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-04     Completed Date:  2013-08-05     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  733-41     Citation Subset:  IM    
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MeSH Terms
Bone Morphogenetic Protein Receptors, Type II / genetics,  metabolism
Cell Proliferation / drug effects
Codon, Nonsense
Epoprostenol / analogs & derivatives*,  pharmacology
HEK293 Cells
Hypertension, Pulmonary / metabolism,  pathology*
Lung / drug effects,  metabolism,  pathology
MAP Kinase Signaling System*
Monocrotaline / pharmacology
Myocytes, Smooth Muscle / drug effects,  metabolism
Protein-Serine-Threonine Kinases / genetics,  metabolism
Rats, Sprague-Dawley
Receptors, Transforming Growth Factor beta / genetics,  metabolism
Smad3 Protein / genetics,  metabolism
Transforming Growth Factor beta1 / antagonists & inhibitors*
Grant Support
1-2004-357//British Heart Foundation; RG/08/006/25302//British Heart Foundation; //Department of Health
Reg. No./Substance:
0/Codon, Nonsense; 0/Receptors, Transforming Growth Factor beta; 0/Smad3 Protein; 0/Smad3 protein, mouse; 0/Transforming Growth Factor beta1; 0/treprostinil; 35E3NJJ4O6/beraprost; 73077K8HYV/Monocrotaline; DCR9Z582X0/Epoprostenol; EC Kinases; EC protein, mouse; EC Morphogenetic Protein Receptors, Type II; EC growth factor-beta type II receptor

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