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Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo.
Circ Res. 2010 Jul 23; 107(2):252-62.CircR

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 Smad1/5-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.

Authors+Show Affiliations

Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospital, Cambridge CB20QQ, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20522807

Citation

Yang, Jun, et al. "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, vol. 107, no. 2, 2010, pp. 252-62.
Yang J, Li X, Al-Lamki RS, et al. Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo. Circ Res. 2010;107(2):252-62.
Yang, J., Li, X., Al-Lamki, R. S., Southwood, M., Zhao, J., Lever, A. M., Grimminger, F., Schermuly, R. T., & Morrell, N. W. (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), 252-62. https://doi.org/10.1161/CIRCRESAHA.109.209940
Yang J, et al. Smad-dependent and Smad-independent Induction of Id1 By Prostacyclin Analogues Inhibits Proliferation of Pulmonary Artery Smooth Muscle Cells in Vitro and in Vivo. Circ Res. 2010 Jul 23;107(2):252-62. PubMed PMID: 20522807.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo. AU - Yang,Jun, AU - Li,Xiaohui, AU - Al-Lamki,Rafia S, AU - Southwood,Mark, AU - Zhao,Jing, AU - Lever,Andrew M, AU - Grimminger,Friedrich, AU - Schermuly,Ralph T, AU - Morrell,Nicholas W, Y1 - 2010/06/03/ PY - 2010/6/5/entrez PY - 2010/6/5/pubmed PY - 2010/8/25/medline SP - 252 EP - 62 JF - Circulation research JO - Circ Res VL - 107 IS - 2 N2 - 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. SN - 1524-4571 UR - https://www.unboundmedicine.com/medline/citation/20522807/Smad_dependent_and_smad_independent_induction_of_id1_by_prostacyclin_analogues_inhibits_proliferation_of_pulmonary_artery_smooth_muscle_cells_in_vitro_and_in_vivo_ L2 - https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.109.209940?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -