Roles of glutathione and glutathione peroxidase in the protection against endothelial cell injury induced by 15-hydroperoxyeicosatetraenoic acid.
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.
Ochi
H
H
Section of Physiological Chemistry, Faculty of Dentistry, Tokyo Medical and Dental University, Japan.
Morita
I
I
Murota
S
S
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D002339:Carotid Arteries; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism*; D054833:Isoindoles; D007700:Kinetics; D015289:Leukotrienes / Q000494:pharmacology*; D008054:Lipid Peroxides / Q000494:pharmacology*; D008298:Maleates / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D011761:Pyrrolidonecarboxylic Acid; D012643:Selenium / Q000494:pharmacology; D018038:Sodium Selenite; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines
D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D015289:Leukotrienes; D008054:Lipid Peroxides; D008298:Maleates; D016566:Organoselenium Compounds; D013844:Thiazoles; D053778:Thiazolidines; D008717:Methionine Sulfoximine; C042986:ebselen; D019328:Buthionine Sulfoximine; C025086:15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; D005979:Glutathione Peroxidase; C014476:diethyl maleate; D005978:Glutathione; D012643:Selenium; D018038:Sodium Selenite; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid