title: Key Role of ROS in the Process of 15-Lipoxygenase/15-Hydroxyeicosatetraenoiccid-Induced Pulmonary Vascular Remodeling in Hypoxia Pulmonary Hypertension.
abstract: We previously reported that 15-lipoxygenase (15-LO) and its metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) were up-regulated in pulmonary arterial cells from both pulmonary artery hypertension patients and hypoxic rats and that these factors mediated the progression of pulmonary hypertension (PH) by affecting the proliferation and apoptosis of pulmonary arterial (PA) cells. However, the underlying mechanisms of the remodeling induced by 15-HETE have remained unclear. As reactive oxygen species (ROS) and 15-LO are both induced by hypoxia, it is possible that ROS are involved in the events of hypoxia-induced 15-LO expression that lead to PH. We employed immunohistochemistry, tube formation assays, bromodeoxyuridine (BrdU) incorporation assays, and cell cycle analyses to explore the role of ROS in the process of 15-HETE-mediated hypoxic pulmonary hypertension (HPH). We found that exogenous 15-HETE facilitated the generation of ROS and that this effect was mainly localized to mitochondria. In particular, the mitochondrial electron transport chain and nicotinamide-adenine dinucleotide phosphate oxidase 4 (Nox4) were responsible for the significant 15-HETE-stimulated increase in ROS production. Moreover, ROS induced by 15-HETE stimulated endothelial cell (EC) migration and promoted pulmonary artery smooth muscle cell (PASMC) proliferation under hypoxia via the p38 MAPK pathway. These results indicated that 15-HETE-regulated ROS mediated hypoxia-induced pulmonary vascular remodeling (PVR) via the p38 MAPK pathway.
authors.affiliation: Department of Pharmaceutical Analysis, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China.|Biological Sciences, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang Province, China.|Bio-pharmaceutical Key Laboratory of Harbin, Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Min
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Pharmaceutical Analysis, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Pharmacy, the Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang Province, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Sheng
authors.affiliation: Department of Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang Province, China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Analysis, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Harbin Medical University-Daqing, Daqing, Heilongjiang Province, China.|Bio-pharmaceutical Key Laboratory of Harbin, Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D066253:Vascular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D017382:Reactive Oxygen Species; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001093:Arachidonate 15-Lipoxygenase; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C498911:Nox4 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases