15-hydroperoxy-5-8-11-13-eicosatetraenoic-acid and ebselen

We investigated the role of the glutathione redox cycle in endothelial cell injury induced by 15(S)-hydroperoxyeicosatetraenoic acid (15-HPETE), an arachidonate lipoxygenase product. Pretreatment of endothelial monolayers with reduced glutathione (GSH) markedly suppressed 15-HPETE-induced cellular injury, which was determined by the 51Cr-release assay. 15-HPETE-induced cytotoxicity was modified by several GSH-modulating agents such as buthionine sulfoximine and 2-oxothiazolidine-4-carboxylate, indicating that this cyto-protective action of GSH was correlated with the intracellular GSH level. These GSH-modulating agents also modified the conversion of 15-HPETE to 15(S)-hydroxyeicosatetraenoic acid by endothelial cells. On the other hand, the exposure of endothelial cell monolayers to 15-HPETE did not deplete intracellular GSH levels but decreased GSH peroxidase activity. In addition, sodium selenite and ebselen, a stimulator and mimic of GSH peroxidase activity, respectively, displayed remarkable protective effects against 15-HPETE-induced cytotoxicity. These results suggest that intracellular GSH plays a pivotal role in the protection against 15-HPETE-induced endothelial cell injury, and that the decreased activity of GSH peroxidase activity is involved in 15-HPETE-induced cytotoxicity.

Topics: Animals; Antioxidants; Azoles; Buthionine Sulfoximine; Carotid Arteries; Cattle; Cells, Cultured; Endothelium, Vascular; Glutathione; Glutathione Peroxidase; Isoindoles; Kinetics; Leukotrienes; Lipid Peroxides; Maleates; Methionine Sulfoximine; Organoselenium Compounds; Oxidation-Reduction; Pyrrolidonecarboxylic Acid; Selenium; Sodium Selenite; Thiazoles; Thiazolidines