title: Inhibition of overactive transforming growth factor-β signaling by prostacyclin analogs in pulmonary arterial hypertension.
abstract: 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.
authors: Department of Medical and Molecular Genetics, School of Medicine, King's College London, London, United Kingdom.
authors: Takeshi
authors: T
authors: Ogo
authors: H M
authors: HM
authors: Chowdhury
authors: Jun
authors: J
authors: Yang
authors: Lu
authors: L
authors: Long
authors: Xiaohui
authors: X
authors: Li
authors: Yamila N
authors: YN
authors: Torres Cleuren
authors: Nicholas W
authors: NW
authors: Morrell
authors: Ralph T
authors: RT
authors: Schermuly
authors: Richard C
authors: RC
authors: Trembath
authors: Md Talat
authors: MT
authors: Nasim
mesh_terms: D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018389:Codon, Nonsense; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D065627:Familial Primary Pulmonary Hypertension; D057809:HEK293 Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D016686:Monocrotaline / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors*
chemical_list: D018389:Codon, Nonsense; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; C048081:beraprost; D016686:Monocrotaline; D011464:Epoprostenol; D017346:Protein Serine-Threonine Kinases; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II; D000077294:Receptor, Transforming Growth Factor-beta Type II; C427248:treprostinil