Bosentan reverses the hypoxia-induced downregulation of the bone morphogenetic protein signaling in pulmonary artery smooth muscle cells

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• 作者：Hidekazu Maruyama^a ; ^{hide-maruyama06@ob.md.tsukuba.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Cé ; line Dewachter^a ; Satoshi Sakai^b ; Asmae Belhaj^c ; Benoit Rondelet^c ; Myriam Remmelink^d ; Jean-Luc Vachié ; ry^e ; Robert Naeije^a ; Laurence Dewachter^a
• 关键词：Cobalt chloride ; Hypoxia ; Endothelin ; BMPR-2 ; Pulmonary artery smooth muscle cells
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：159
• 期：Complete
• 页码：111-115
• 全文大小：492 K

文摘

Pulmonary hypertension (PH) is a common complication of chronic hypoxic lung diseases. Bone morphogenetic protein (BMP) and endothelin-1 signaling pathways have been shown to be altered in hypoxic PH and to play crucial roles in the associated pulmonary artery remodeling. We, therefore, aimed to study the potential link between hypoxia and the alteration of BMP and endothelin-1 signaling observed in pulmonary artery smooth muscle cells (PA-SMCs) in hypoxic PH.

Materials and Methods

Human PA-SMCs were treated with hypoxia-mimetic agent cobalt chloride (CoCl₂; 100 μM), with or without pretreatment with a dual endothelin receptor antagonist bosentan (10 μM). Expressions of preproendothelin-1 (PPET1), BMP type 2 receptor (BMPR-2), and one BMP signaling target gene, the inhibitor of DNA binding 1 (ID1) were evaluated by real time quantitative polymerase chain reaction. BMP2-treated PA-SMCs were assessed for Smad1/5/8 signaling activation by Western Blotting.

Key findings

Treatment of PA-SMCs with CoCl₂ increased PPET1 gene expression, while it did not alter expressions of endothelin converting enzyme, endothelin receptor type A or type B. Hypoxia-mimetic agent CoCl₂ decreased the expressions of BMPR-2 and ID1 maximally after 3- and 6-hour treatment respectively, while CoCl₂ treatment progressively increased noggin expression. Bosentan pretreatment restored expressions of BMPR-2 and ID1, as well as the activation (by phosphorylation) of Smad1/5/8 signaling induced by BMP2.

Significance

Hypoxia induces the downregulation of the BMP signaling in PA-SMCs, at least, partly through the endothelin system. In hypoxic PH, increased endothelin-1 production might therefore contribute to the altered BMP signaling and subsequent PA-SMC hyperplasia.