title: 15-Lipoxygenase promotes chronic hypoxia-induced pulmonary artery inflammation via positive interaction with nuclear factor-κB.
abstract: OBJECTIVE
  Our laboratory has previously demonstrated that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) is involved in hypoxic pulmonary arterial hypertension. Chronic hypoxia-induced vascular inflammation has been considered as an important stage in the development of pulmonary arterial hypertension. Here, we determined the contribution of 15-HETE in the hypoxia-induced pulmonary vascular inflammation.
  
  
  RESULTS
  Chronic hypoxia-induced monocyte/macrophage infiltration and the expressions of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were analyzed in hypoxic rat model and cultured pulmonary arterial endothelium cells using immunochemistry methods. We found that monocyte/macrophage infiltration and the expressions of intercellular adhesion molecules under hypoxia were markedly inhibited by 15-HETE inhibitors or 15-LO1/2 small interfering RNA. In addition, exogenous 15-HETE enhanced the expression of both adhesion molecules in pulmonary arterial endothelium cells in a time-dependent manner. Hypoxia-induced 15-LO1/2 expression in rat pulmonary arterial endothelium cells was significantly abolished by nuclear factor-κB inhibitors. Meanwhile, nuclear factor-κB activity was enhanced prominently by the 15-LO1/2 product, 15-HETE, suggesting a positive feedback mechanism.
  
  
  CONCLUSIONS
  Taken together, our results suggest that chronic hypoxia promotes monocyte infiltration into the vasculature and adhesion molecules upregulation in pulmonary arterial endothelium cells via a positive interaction between 15-LO/15-HETE and nuclear factor-κB. Our study revealed a novel mechanism underlying hypoxia-induced pulmonary arterial inflammation and suggested new therapeutic strategies targeting 15-LO/15-HETE and nuclear factor-κB in the treatment of pulmonary arterial hypertension.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University-Daqing, Daqing, Heilongjiang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Jingjing
authors.initials: J
authors.lastname: Rao
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Cao
authors.forename: Yueming
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qianlong
authors.initials: Q
authors.lastname: Zhang
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000502:physiology*; D001167:Arteritis / Q000473:pathology*; D002478:Cells, Cultured; D002908:Chronic Disease; D006893:Hydroxyeicosatetraenoic Acids / Q000502:physiology; D000860:Hypoxia / Q000473:pathology*; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D008297:Male; D009000:Monocytes / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D011651:Pulmonary Artery / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001093:Arachidonate 15-Lipoxygenase