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 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 approximately 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.
Sevanian
A
A
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, Los Angeles, CA 90033, USA.
Hwang
J
J
Hodis
H
H
Cazzolato
G
G
Avogaro
P
P
Bittolo-Bon
G
G
D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D001161:Arteriosclerosis / Q000097:blood / Q000453:epidemiology; D001205:Ascorbic Acid / Q000494:pharmacology; D002499:Centrifugation, Density Gradient; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D006801:Humans; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000097:blood* / Q000145:classification / Q000302:isolation & purification; D010084:Oxidation-Reduction; D012307:Risk Factors; D014810:Vitamin E / Q000032:analysis
D000975:Antioxidants; D008077:Lipoproteins, LDL; D014810:Vitamin E; D001205:Ascorbic Acid