{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:23:13Z","timestamp":1790504593857,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2013,6,1]],"date-time":"2013-06-01T00:00:00Z","timestamp":1370044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The heterozygous loss of function mutations in the Type II bone morphogenetic protein receptor (BMPR-II), a member of the transforming growth factor (TGF-\u03b2) receptor family, underlies the majority of familial cases of pulmonary arterial hypertension (PAH). The TGF-\u03b21 pathway is activated in PAH, and inhibitors of TGF-\u03b21 signaling prevent the development and progression of PAH in experimental models. However, the effects of currently used therapies on the TGF-\u03b2 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-\u03b21 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-\u03b21 stimulation. Our study demonstrates that this agent inhibits TGF-\u03b21\u2013induced SMAD-dependent and SMAD-independent signaling via a protein kinase A\u2013dependent 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-\u03b2 signaling, this study confirms that treprostinil, a stable prostacyclin analog, inhibits the TGF-\u03b2 pathway by reducing SMAD3 phosphorylation. Taken together, these data suggest that prostacyclin analogs inhibit dysregulated TGF-\u03b2 signaling in vitro and in vivo, and reduce BMPR-II\u2013mediated proliferation defects in mutant mice PASMCs.<\/jats:p>","DOI":"10.1165\/rcmb.2012-0049oc","type":"journal-article","created":{"date-parts":[[2013,2,15]],"date-time":"2013-02-15T22:23:49Z","timestamp":1360967029000},"page":"733-741","source":"Crossref","is-referenced-by-count":52,"title":["Inhibition of Overactive Transforming Growth Factor\u2013\u03b2 Signaling by Prostacyclin Analogs in Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"48","author":[{"given":"Takeshi","family":"Ogo","sequence":"first","affiliation":[{"name":"Department of Medical and Molecular Genetics, School of Medicine, and"},{"name":"Division of Cardiology, Department of Pulmonary Circulation, National Cerebral and Cardiovascular Center Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. M.","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Long","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamila N.","family":"Torres Cleuren","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas W.","family":"Morrell","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph T.","family":"Schermuly","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Justus-Liebig University, Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C.","family":"Trembath","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. 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