© 1996 American Heart Association, Inc.
Articles |
Contribution of an In Vivo Oxidized LDL to LDL Oxidation and Its Association With Dense LDL Subpopulations
From the Department of Molecular Pharmacology and Toxicology (A.S., J.H., H.H.), School of Pharmacy, and the Atherosclerosis Research Unit (A.S., H.H.), Division of Cardiology, University of Southern California, Los Angeles, Calif, and the Centro Regionale Specializzato per l'Arteriosclerosi (G.C., G.B.-B.), Servizio di Diabetologia, Ospedale Riuniti, Venezia, Italy.
Correspondence to Alex Sevanian, University of Southern California, Department of Molecular Pharmacology and Toxicology, School of Pharmacy, 1985 Zonal Ave, PSC 612, Los Angeles, CA 90033.
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.
Key Words: lipid peroxidation • peroxides • ascorbic acid • heme
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