Journal article

Publication year: 2010

Pages: 252-U170

Journal: Circulation Research

Volume number: 107

Issue number: 2

ISSN: 0009-7330

eISSN: 1524-4571

Open access status: Bronze

DOI Link: https://doi.org/10.1161/CIRCRESAHA.109.209940

Publisher: American Heart Association

Abstract: 

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 Smad1/5driven 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. (Circ Res. 2010; 107:252-262.)

Harvard Citation style: Yang, J., Li, X., Al-Lamki, R., Southwood, M., Zhao, J., Lever, A., et al. (2010) Smad-Dependent and Smad-Independent Induction of Id1 by Prostacyclin Analogues Inhibits Proliferation of Pulmonary Artery Smooth Muscle Cells In Vitro and In Vivo, Circulation Research, 107(2), pp. 252-U170. https://doi.org/10.1161/CIRCRESAHA.109.209940

APA Citation style: Yang, J., Li, X., Al-Lamki, R., Southwood, M., Zhao, J., Lever, A., Grimminger, F., Schermuly, R., & Morrell, N. (2010). Smad-Dependent and Smad-Independent Induction of Id1 by Prostacyclin Analogues Inhibits Proliferation of Pulmonary Artery Smooth Muscle Cells In Vitro and In Vivo. Circulation Research. 107(2), 252-U170. https://doi.org/10.1161/CIRCRESAHA.109.209940