IN-VITRO CELL INJURY BY OXIDIZED LOW-DENSITY-LIPOPROTEIN INVOLVES LIPID HYDROPEROXIDE-INDUCED FORMATION OF ALKOXYL, LIPID, AND PEROXYL RADICALS

Mounting evidence supports current theories linking lipoprotein oxidat ion to atherosclerosis, We sought the cellular biochemical mechanism b y which oxidized LDL inflicts cell injury, Inhibitors of candidate pat hways of cell death were used to treat human fibroblast target cells e xposed to oxidized LDL, Ebselen, which degrades lipid hydroperoxides, inhibited oxidized LDL toxicity, consistent with our recent report tha t 7 beta-hydroperoxycholesterol (7 beta-OOH chol) is the major cytotox in of oxidized LDL, Intracellular chelation of metal ions inhibited, w hile preloading cells with iron enhanced, toxicity, Inhibition of oxid ized LDL and 7 beta-OOH chol toxicity by 2-keto-3-thiolmethyl butyric acid, a putative alkoxyl radical scavenger and by vitamin E, probucol and diphenylphenylenediamine, putative scavengers of peroxyl radicals was consistent with the involvement of these radicals in the lethal se quence. Cell death was thus postulated to occur due to lipid peroxidat ion,ia a sequence involving lipid hydroperoxide-induced, iron-mediated formation of alkoxyl, lipid, and peroxyl radicals, Path trays involvi ng other reactive oxygen species, new protein synthesis, or altered ch olesterol metabolism were considered less likely, since putative inhib itors failed to lessen toxicity, Understanding the mechanism of cell i njury by oxidized LDL and its toxic moiety, 7 beta-OOH chol, may indic ate specific interventions in the cell injury believed to accompany va scular lesion development.