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

Am J Respir Cell Mol Biol. 2013 Jun;48(6):733-41. doi: 10.1165/rcmb.2012-0049OC.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Cell Proliferation / drug effects
  • Codon, Nonsense
  • Epoprostenol / analogs & derivatives*
  • Epoprostenol / pharmacology
  • Familial Primary Pulmonary Hypertension
  • HEK293 Cells
  • Humans
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / pathology*
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • MAP Kinase Signaling System*
  • Male
  • Mice
  • Monocrotaline / pharmacology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta1 / antagonists & inhibitors*


  • Codon, Nonsense
  • Receptors, Transforming Growth Factor beta
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta1
  • beraprost
  • Monocrotaline
  • Epoprostenol
  • Protein Serine-Threonine Kinases
  • Bmpr2 protein, mouse
  • Bone Morphogenetic Protein Receptors, Type II
  • Receptor, Transforming Growth Factor-beta Type II
  • treprostinil