Contribution of an in vivo oxidized LDL to LDL oxidation and its association with dense LDL subpopulations

Oxidative modification of LDL is thought to be a radical-mediated process involving lipid peroxides. The small dense LDL subpopulations are particularly susceptible to oxidation, and individuals with high proportions of dense LDL are at a greater risk for atherosclerosis. An oxidatively modified plasma LDL. referred to as LDL(-). is found largely among the dense LDL fractions. LDL(-) and dense LDL particles also contain much greater amounts of lipid peroxides compared with total LDL or the mure buoyant LDL fractions. The content of LDL(-) in dense LDL particles appears to be related to copper- or heme-induced oxidative susceptibility, which may be attributable to peroxide levels. The rate of lipid peroxidation during the antioxidant-protected phase (lag period) and the length of the antioxidant-protected phase (lag time) are correlated with the LDL(-) content of total LDL. Once LDL oxidation enters the propagation phase, there is no relationship to the initial LDL(-) content or total LDL lipid peroxide or vitamin E levels. Beyond a threshold LDL(-) content of approximate to 2%, there is a significant increase in the oxiative susceptibility of nLDL particles (ie, purified LDL that is free of LDL(-)), and this susceptibility becomes more pronounced as the LDL(-) content increases, nLDL is resistant to copper- or heme-induced oxidation. The oxidative susceptibility is not influenced by Vitamin E content in LDL bur is strongly inhibited by ascorbic acid in the medium. involvement of LDL(-)-associated peroxides during the stimulated oxidation of LDL is suggested by the inhibition of nLDL oxidation when LDL(-) is treated with ebselen prior to its addition to nLDL. Populations of LDL enriched with LDL(-) appear to contain peroxides at levels approaching the threshold required for progressive radical propagation reactions. We postulate that elevated LDL(-) may constitute a pro-oxidant state that facilitates oxidative reactions in vascular components.