title: 15-Lipoxygenase and 15-hydroxyeicosatetraenoic acid regulate intravascular thrombosis in pulmonary hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a disease characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, pulmonary vascular thrombotic lesions, and right heart failure. Recent studies suggest that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) play an important role in PAH, acting on arterial walls. Here, we show evidence for the action of the 15-LO/15-HETE signaling in the pulmonary vascular thrombotic lesions in the experimental PAH models. Platelet deposition was augmented in rats exposed to hypoxia and Sugen 5416, which were both prevented by nordihydroguaiaretic acid (NDGA), a 15-LO inhibitor. Chronic hypoxic resulted in the platelet deposition specifically in pulmonary vasculature, which was reversed by 15-LO inhibitor. The 15-LO pathway mediated in the endothelial dysfunction induced by hypoxia in vivo. Meanwhile, 15-HETE positively regulated the generation of IL-6 and monocyte chemoattractant protein-1 (MCP-1). The coagulation and platelet activation induced by hypoxia were reversed by 15-LO inhibitor NDGA or the MCP-1 inhibitor synthesis inhibitor bindarit in rats. The 15-LO/15-HETE signaling promoted the coagulation and platelet activation, which was suppressed by MCP-1 inhibition. These results therefore suggest that 15-LO/15-HETE signaling plays a role in platelet activation and pulmonary vascular thrombosis in PAH, involving MCP-1.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China;
authors.forename: Tingting
authors.initials: T
authors.lastname: Shen
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China;
authors.forename: Jiucheng
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China;
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China;
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China;
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China;
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China;
authors.forename: Liuping
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China;
authors.forename: Cui
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China;
authors.forename: Xijuan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China;
authors.forename: Mingming
authors.initials: M
authors.lastname: Lian
authors.affiliation: Biology Department, Georgia State University, Atlanta, Georgia.
authors.forename: Chun
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China; Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, China; and dalingz@yahoo.com.
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000473:pathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000473:pathology*; D000860:Hypoxia / Q000097:blood / Q000473:pathology; D007191:Indazoles / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use; D008297:Male; D009637:Masoprocol / Q000627:therapeutic use; D015539:Platelet Activation / Q000187:drug effects; D011422:Propionates / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016207:Cytokines; D006893:Hydroxyeicosatetraenoic Acids; D007191:Indazoles; D016859:Lipoxygenase Inhibitors; D011422:Propionates; D034741:RNA, Small Interfering; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D009637:Masoprocol; D001093:Arachidonate 15-Lipoxygenase; C079489:bindarit
keywords: 15-lipoxygenase; monocyte chemoattractant protein-1; platelet; thrombosis