Content of antioxidants, preformed lipid hydroperoxides, and cholesterol as predictors of the susceptibility of human LDL to metal ion-dependent and -independent oxidation

Oxidative modification of low density lipoprotein (LDL) has been suggested to play a casual role in human atherosclerosis, and prevention of LDL oxidation may be an effective strategy to prevent or slow the progression of this disease. It is important, therefore, to identify the factors that determine LDL's susceptibility to oxidation. We have analyzed 62 human LDL samples for content of antioxidants, preformed lipid hydroperoxides, and cholesterol. To investigate their oxidative susceptibility, the LDL samples were exposed to either a metal ion-dependent (Cu2+) or -independent (aqueous peroxyl radicals) oxidizing system; the length of the lag phase of inhibited lipid peroxidation was measured, as well as the rate of lipid peroxidation during the lag and ensuing propagation phases. The susceptibility of LDL to metal ion-dependent oxidation was not related to its susceptibility to metal ion-independent oxidation. A strong predictor of an increased susceptibility of LDL to metal ion-dependent oxidation was a decreased vitamin E-to-cholesterol ratio, in contrast to the vitamin E-to-protein ratio. Elevated levels of performed lipid hydroperoxides in LDL and an increased cholesterol content were also associated with an increased susceptibility of the lipoprotein to Cu2+-induced oxidation. Remarkably, a strong predictor of an increased susceptibility of LDL to metal ion-independent oxidation was an increased, rather than decreased, vitamin E content relative to protein. An increased cholesterol content also was associated with an increased oxidative susceptibility of LDL to aqueous peroxyl radicals, while preformed lipid hydroperoxides showed no significant correlation. Ubiquinol-10, beta-carotene, and lycopene, whether quantitated relative to cholesterol or protein, did not show significant protective effects against both metal ion-dependent and -independent oxidation of LDL. Our data suggest that a high lipid content of LDL, relative to its protein content, renders the lipoprotein more susceptible to oxidative modification, while vitamin E may have either a protective or promoting effect on LDL oxidation, depending on the oxidative stress conditions. Other known antioxidants in LDL do not appear to play a significant role in protecting LDL against oxidative modification.