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Cell signalling and cell responses in pulmonary vascular disease
S150 Smad-dependent and Smad-independent induction of Id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo
  1. Jun Yang,
  2. Xiaohui Li,
  3. Rafia S Al-Lamki,
  4. Mark Southwood,
  5. Jing Zhao,
  6. Andrew M Lever,
  7. Friedrich Grimminger,
  8. Ralph T Schermuly,
  9. Nicholas W Morrell
  1. University of Cambridge, Cambridge, UK

Abstract

Introduction and Objectives Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for the majority of cases of heritable pulmonary arterial hypertension (PAH). Mutations lead to reduced Smad1/5-driven expression of inhibitor of DNA binding protein 1 (Id1) and loss of the growth suppressive effects of BMPs. The impact of existing PAH therapies on BMP signalling is lacking. Because prostacyclin analogues are effective treatments for clinical PAH, we hypothesised that these agents enhance Smad1/Id1 signalling.

Methods Iloprost alone induced Id1 expression in human pulmonary artery smooth muscle cells (PASMCs), an effect that was independent of Smad1/5 activation but dependent on a cAMP-responsive element in the Id1 promoter. In addition, iloprost and treprostinil enhanced BMP-induced phosphorylation of Smad1/5 and Id1 expression in a cAMP-dependent manner. The mechanism involved suppression of inhibitory Smad, Smad6. Furthermore, iloprost rescued the deficit in Smad1/5 phosphorylation and Id gene expression in PASMCs harbouring mutations in BMPR-II and restored growth suppression to BMP4 in mutant PASMCs.

Results We confirmed a critical role for Id1 in PASMC proliferation. Reduced expression of Id1 was observed in concentric intimal lesions of heritable PAH cases. In the monocrotaline rat model of PAH, associated with reduced BMPR-II expression, we confirmed that treprostinil inhibited smooth muscle cell proliferation and prevented progression of PAH while enhancing Smad1/5 phosphorylation and Id1 gene expression.

Conclusions Prostacyclin analogues enhance Id1 expression in vitro and in vivo and restore deficient BMP signalling in BMPR-II mutant PASMCs.

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