title: Bosentan reverses the hypoxia-induced downregulation of the bone morphogenetic protein signaling in pulmonary artery smooth muscle cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Human PA-SMCs were treated with hypoxia-mimetic agent cobalt chloride (CoCl2; 100μM), with or without pretreatment with a dual endothelin receptor antagonist bosentan (10μM). 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Physiology and Pharmacology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium,. Electronic address: hide-maruyama06@ob.md.tsukuba.ac.jp.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Maruyama
authors.affiliation: Laboratory of Physiology and Pharmacology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Céline
authors.initials: C
authors.lastname: Dewachter
authors.affiliation: Division of Cardiovascular Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakai
authors.affiliation: Department of Thoracic Surgery, Erasmus University Hospital, Brussels, Belgium.
authors.forename: Asmae
authors.initials: A
authors.lastname: Belhaj
authors.affiliation: Department of Thoracic Surgery, Erasmus University Hospital, Brussels, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Rondelet
authors.affiliation: Department of Anatomopathology, Erasmus University Hospital, Brussels, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Remmelink
authors.affiliation: Department of Cardiology, Erasmus University Hospital, Brussels, Belgium.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Vachiéry
authors.affiliation: Laboratory of Physiology and Pharmacology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Naeije
authors.affiliation: Laboratory of Physiology and Pharmacology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Dewachter
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D000077300:Bosentan; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D019485:Bone Morphogenetic Proteins; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D003035:Cobalt; C018021:cobaltous chloride; D000077300:Bosentan
keywords: BMPR-2; Cobalt chloride; Endothelin; Hypoxia; Pulmonary artery smooth muscle cells