Key Role of ROS in the Process of 15-Lipoxygenase/15-Hydroxyeicosatetraenoiccid-Induced Pulmonary Vascular Remodeling in Hypoxia Pulmonary Hypertension

• Published in: PloS one Vol. 11; no. 2; p. e0149164
• Main Authors: Li, Qian, Mao, Min, Qiu, Yanli, Liu, Gaofeng, Sheng, Tingting, Yu, Xiufeng, Wang, Shuang, Zhu, Daling
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.02.2016; Public Library of Science (PLoS)
• Subjects: Adenine; Analysis; Animals; Apoptosis; Arachidonate 15-Lipoxygenase - metabolism; Biology and Life Sciences; Bromodeoxyuridine; Cattle; Cell cycle; Cell proliferation; Cells, Cultured; Development and progression; Electron transport; Electron transport chain; Endothelial cells; Female; Gene expression; Genetic aspects; Humans; Hydroxyeicosatetraenoic Acids - metabolism; Hypertension; Hypertension, Pulmonary - complications; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - physiopathology; Hypoxia; Hypoxia - complications; Hypoxia - metabolism; Hypoxia - physiopathology; Immunoglobulins; Immunohistochemistry; Kinases; Laboratory animals; Lipoxygenase; Lung - blood supply; Lung - pathology; Lung - physiopathology; MAP kinase; Medicine and Health Sciences; Mitochondria; NAD; NADPH Oxidase 4; NADPH Oxidases - analysis; NADPH Oxidases - metabolism; NADPH-diaphorase; Nicotinamide; NOX4 protein; Oxidase; Oxidative stress; Oxygen; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmaceuticals; Pharmacy; Phosphates; Physiological aspects; Pulmonary arteries; Pulmonary artery; Pulmonary hypertension; Rats; Rats, Wistar; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; Signal Transduction; Smooth muscle; Vascular Remodeling; Veins & arteries; United States; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0149164

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.