title: Participation of the arachidonic acid cascade pathway in macrophage binding/uptake of oxidized low density lipoprotein.
abstract: Arachidonic acid cascade inhibitors, including phospholipase A2 inhibitors, dexamethasone and quinacrine (mepacrine), cyclooxygenase inhibitors, indomethacin and aspirin, and lipoxygenase inhibitor AA861, prevented foam cell formation and cholesterol accumulation in the incubation of thioglycollate-induced mouse peritoneal macrophages with oxidized low density lipoprotein (LDL) at 37 degrees C for 24 h. These inhibitors similarly prevented foam cell formation of fibronectin- and Ca ionophore A23187-stimulated macrophages. Binding and/or uptake of Dil (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine)-acetyl LDL by macrophages at 37 degrees C for 3h and arachidonic acid release from macrophages at 37 degrees C for 4h were inhibited by dexamethasone. Exogenously added phospholipase A2 of bee venom and Crotalus adamanteous venom increased arachidonic acid release during incubation for 2 h, and increased macrophage binding and/or uptake of Dil-acetyl LDL at 37 degrees C for 3 h, and foam cell formation at 37 degrees C for 24 h. Protein kinase inhibitors, ML-9 and staurosporine, that inhibited macrophage binding and/or uptake of Dil-acetyl LDL did not inhibit arachidonic acid release, indicating that protein phosphorylation was not involved in the arachidonic acid pathway in the macrophage scavenger receptor activation. Nordihydroguaiaretic acid that inhibited arachidonic acid release prevented binding and/or uptake of Dil-acetyl LDL. The release of arachidonic acid was not enhanced by fibronectin-stimulation, indicating that Ca influx-dependent stimulation of macrophage activity was not through the activation of phospholipase A2. These results indicate that, as well as the fibronectin-stimulated Ca influx pathway and protein phosphorylation pathway, the arachidonic acid pathway participated in the activation of macrophages to bind and take up oxidized LDL.
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Beppu
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Watanabe
authors.forename: Masaru
authors.initials: M
authors.lastname: Sunohara
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohishi
authors.forename: Eriko
authors.initials: E
authors.lastname: Mishima
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kawachi
authors.forename: Motohiro
authors.initials: M
authors.lastname: Fujii
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Kikugawa
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice; D010084:Oxidation-Reduction; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D054467:Phospholipases A2; D010766:Phosphorylation
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005353:Fibronectins; D008077:Lipoproteins, LDL; D016718:Arachidonic Acid; D009637:Masoprocol; D003907:Dexamethasone; D002784:Cholesterol; D010741:Phospholipases A; D054467:Phospholipases A2