title: Enhanced 15-HPETE production during oxidant stress induces apoptosis of endothelial cells.
abstract: Oxidant stress plays an important role in the etiology of vascular diseases by increasing rates of endothelial cell apoptosis, but few data exist on the mechanisms involved. Using a unique model of oxidative stress based on selenium deficiency (-Se), the effects of altered eicosanoid production on bovine aortic endothelial cells (BAEC) apoptosis was evaluated. Oxidant stress significantly increased the immediate oxygenation product of arachidonic acid metabolized by the 15-lipoxygenase pathway, 15-hydroxyperoxyeicosatetraenoic acid (15-HPETE). Treatment of -Se BAEC with TNFalpha/cyclohexamide (CHX) exhibited elevated levels of apoptosis, which was significantly reduced by the addition of a specific 15-lipoxygenase inhibitor PD146176. Furthermore, the addition of 15-HPETE to PD146176-treated BAEC, partially restored TNF/CHX-induced apoptosis. Increased exposure to 15-HPETE induced apoptosis, as determined by internucleosomal DNA fragmentation, chromatin condensation, caspase-3 activation, and caspase-9 activation, which suggests mitochondrial dysfunction. The expression of Bcl-2 protein also was decreased in -Se BAEC. Addition of a caspase-9 inhibitor (LEHD-fmk) completely blocked 15-HPETE-induced chromatin condensation in -Se BAEC, suggesting that 15-HPETE-induced apoptosis is caspase-9 dependent. Increased apoptosis of BAEC as a result of oxidant stress and subsequent production of 15-HPETE may play a critical role in a variety of inflammatory based diseases.
authors.affiliation: Large Animal Clinical Sciences, D202 Veterinary Medical Center, College of Veterinary Medicine, Michigan State University, East Lansing, 48824-1314, USA. sordillo@msu.edu
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Sordillo
authors.forename: James A
authors.initials: JA
authors.lastname: Weaver
authors.forename: Yu-Zhang
authors.initials: YZ
authors.lastname: Cao
authors.forename: Chris
authors.initials: C
authors.lastname: Corl
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Sylte
authors.forename: Isis K
authors.initials: IK
authors.lastname: Mullarky
mesh_terms: D000818:Animals; D017209:Apoptosis; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis*; D008054:Lipid Peroxides / Q000096:biosynthesis*; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012643:Selenium / Q000378:metabolism
chemical_list: D015289:Leukotrienes; D008054:Lipid Peroxides; D019253:Proto-Oncogene Proteins c-bcl-2; C025086:15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; D005979:Glutathione Peroxidase; D001093:Arachidonate 15-Lipoxygenase; D053453:Caspase 9; D020169:Caspases; D012643:Selenium