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 proc ess involving lipid peroxides. The small dense LDL subpopulations are particularly susceptible to oxidation, and individuals with high propo rtions of dense LDL are at a greater risk for atherosclerosis. An oxid atively modified plasma LDL. referred to as LDL(-). is found largely a mong the dense LDL fractions. LDL(-) and dense LDL particles also cont ain much greater amounts of lipid peroxides compared with total LDL or the mure buoyant LDL fractions. The content of LDL(-) in dense LDL pa rticles appears to be related to copper- or heme-induced oxidative sus ceptibility, 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 cor related with the LDL(-) content of total LDL. Once LDL oxidation enter s the propagation phase, there is no relationship to the initial LDL(- ) content or total LDL lipid peroxide or vitamin E levels. Beyond a th reshold LDL(-) content of approximate to 2%, there is a significant in crease in the oxiative susceptibility of nLDL particles (ie, purified LDL that is free of LDL(-)), and this susceptibility becomes more pron ounced as the LDL(-) content increases, nLDL is resistant to copper- o r heme-induced oxidation. The oxidative susceptibility is not influenc ed by Vitamin E content in LDL bur is strongly inhibited by ascorbic a cid in the medium. involvement of LDL(-)-associated peroxides during t he 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 perox ides at levels approaching the threshold required for progressive radi cal propagation reactions. We postulate that elevated LDL(-) may const itute a pro-oxidant state that facilitates oxidative reactions in vasc ular components.