title: Elk-1-mediated 15-lipoxygenase expression is required for hypoxia-induced pulmonary vascular adventitial fibroblast dynamics.
abstract: 15-Lipoxygenase (15-LO) is an important factor in the pathogenesis of pulmonary artery hypertension (PAH). However, the role of 15-LO in the adventitia of the pulmonary arterial wall is unclear. The aim of this study was to explore the role of 15-LO in the modulation of pulmonary adventitial fibroblast (PAF) dynamics.
  
  
  
  Rats were exposed to normoxic or hypoxic (fraction of inspired O2= 0.12) treatments for 7 days. PAF proliferation and cell cycle alterations were measured by MTT assay, cell immunofluorescence, flow cytometry and Western blot analysis. The 15-LO promoter was analysed by luciferase reporter and ChIP assays.
  
  
  
  Our results showed that hypoxia induced 15-LO expression in PAFs both in vivo and in vitro. In addition, hypoxia stimulated JNK phosphorylation in PAFs. Blocking 15-LO or JNK suppressed 15-LO-induced PAF proliferation and cell cycle alterations. The inhibition of p27kiplby gene silencing attenuated 15-LO-induced PAF proliferation and cell cycle alterations. Furthermore, JNK inhibition or Elk-1 knockdown suppressed hypoxia-induced 15-LO expression in PAFs. Luciferase reporter and ChIP assays revealed that the 15-LO promoter contains Elk-1-binding sites and also that Elk-1 increased the hypoxia-induced activity of the 15-LO promoter.
  
  
  
  These results suggest that hypoxia promotes changes in the cellular dynamics of PAFs by inducing 15-LO expression, which leads to vascular adventitial remodelling. The modulation of p27kiplexpression by 15-LO enhances PAF proliferation and cell cycle alterations. Furthermore, the JNK-dependent increase in Elk-1 signalling is required for hypoxia-induced 15-LO expression in PAFs.
authors.affiliation: Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China.|Biopharmaceutical Institute of the Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China.
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Biopharmaceutical Institute of the Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang, China.
authors.forename: S
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang, China.|Biopharmaceutical Institute of the Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang, China.
authors.forename: D
authors.initials: D
authors.lastname: Zhu
mesh_terms: D063194:Adventitia / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D011651:Pulmonary Artery / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism*
chemical_list: D050807:ets-Domain Protein Elk-1; D001093:Arachidonate 15-Lipoxygenase
keywords: 15-lipoxygenase; Elk-1; JNK pathway; cell proliferation; pulmonary adventitia fibroblast