Inhibition of overactive transforming growth factor-β signaling by prostacyclin analogs in pulmonary arterial hypertension

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

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 ofPAHin 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 BMPRII- mediated proliferation defects in mutant mice PASMCs. 

Original languageEnglish
Pages (from-to)733-741
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume48
Issue number6
DOIs
Publication statusPublished - 1 Jun 2013

Keywords

  • BMPR2
  • PAH
  • PASMC
  • Prostacyclins
  • Signaling
  • TGF-β

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