FORMATION OF NON-CYCLOOXYGENASE-DERIVED PROSTANOIDS (F-2-ISOPROSTANES) IN PLASMA AND LOW-DENSITY-LIPOPROTEIN EXPOSED TO OXIDATIVE STRESS IN-VITRO

F-2-isoprostanes are prostaglandin F-2-like compounds that are known t o be formed in vivo by free radical oxidation of arachidonyl-containin g lipids, and their plasma levels have been suggested as indicators of in vivo oxidative stress. As oxidation of LDL, a likely causal factor in atherosclerosis, involves lipid peroxidation, we investigated whet her F-2-isoprostanes are formed in plasma and LDL exposed to oxidative stress, and how F-2-isoprostane formation is related to endogenous an tioxidant status. In plasma exposed to aqueous peroxyl radicals, lipid hydroperoxides and esterified F-2-isoprostanes were formed simultaneo usly after endogenous ascorbate and ubiquinol-10 had been exhausted, d espite the continued presence of urate, alpha-tocopherol, beta-caroten e, and lycopene. In isolated LDL exposed to aqueous peroxyl radicals o r Cu2+, consumption of endogenous ubiquinol-10 and alpha-tocopherol wa s followed by rapid formation and subsequent breakdown of lipid hydrop eroxides and esterified F-2-isoprostanes, and a continuous increase in LDL's electronegativity, indicative of atherogenic modification. In C u2+-exposed LDL, the decrease in esterified F-2-isoprostane levels was paralleled by the appearance of free F-2-isoprostanes, suggesting tha t hydrolysis by an LDL-associated activity had occurred. Our data sugg est that F-2-isoprostanes are useful markers of LDL oxidation in vivo. As F-2-isoprostanes are potent vasoconstrictors and can modulate plat elet aggregation, their formation in LDL demonstrated here may also ha ve important implications for the etiology of cardiovascular disease.