Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo

J Yang, X Li, RS Al-Lamki, M Southwood… - Circulation …, 2010 - Am Heart Assoc
J Yang, X Li, RS Al-Lamki, M Southwood, J Zhao, AM Lever, F Grimminger, RT Schermuly…
Circulation research, 2010Am Heart Assoc
Rationale: 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 signaling is lacking. Objective: Because prostacyclin analogues are
effective treatments for clinical PAH, we hypothesized that these agents enhance Smad1/Id1 …
Rationale: 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 signaling is lacking.
Objective: Because prostacyclin analogues are effective treatments for clinical PAH, we hypothesized that these agents enhance Smad1/Id1 signaling.
Methods and Results: 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 harboring mutations in BMPR-II and restored growth suppression to BMP4 in mutant PASMCs. 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 signaling in BMPR-II mutant PASMCs.
Am Heart Assoc