Contribution of an In Vivo Oxidized LDL to LDL Oxidation and Its Association With Dense LDL Subpopulations

Abstract

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 more 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 ≈2%, there is a significant increase in the oxidative 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 but 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.