COMPARATIVE STUDY
JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
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Ascorbic acid oxidation product(s) protect human low density lipoprotein against atherogenic modification. Anti- rather than prooxidant activity of vitamin C in the presence of transition metal ions.

The oxidative modification of low density lipoprotein (LDL) has been proposed as an important causative event in the development of human atherosclerosis. As a corollary of this hypothesis, antioxidants that can prevent LDL oxidation may inhibit atherosclerosis. Oxidative modification of LDL in vitro, either induced by Cu2+ or mediated by cultured arterial wall cells in media containing trace amounts of transition metal ions, is strongly inhibited by vitamin C (L-ascorbic acid (AA)). AA, however, is known to act as a prooxidant rather than an antioxidant in the presence of transition metal ions. We observed that AA is oxidized rapidly when incubated with Cu2+ and LDL, leading to transient formation of dehydro-L-ascorbic acid (DHA). Although AA and DHA can no longer be detected after 3.5 h of incubation, LDL resists oxidative modification for at least 20 h, as assessed by anodic gel electrophoretic mobility. Remarkably, DHA protects LDL more effectively against both Cu(2+)-induced lipid peroxidation and shifts in electrophoretic mobility than does AA; indeed, AA per se, without oxidation to DHA, offers no protection. By inhibiting oxidative modification of LDL, AA and DHA prevent uptake of LDL by macrophages via the scavenger receptor pathway. When LDL is incubated with DHA followed by gel filtration, LDL remains protected against subsequent Cu(2+)-induced oxidative modification, suggestive of stable modification of LDL in the presence of DHA. In contrast, DHA is ineffective against a metal ion-independent type of oxidative stress, viz. aqueous peroxyl radicals; under these conditions, only AA is able to inhibit lipid peroxidation in LDL. Our data indicate that vitamin C protects LDL against atherogenic modification by two different mechanisms that may act in concert: (i) free radical scavenging by AA prevents aqueous oxidants from attacking and oxidizing LDL, and (ii) stable modification of LDL by DHA or decomposition product(s) thereof imparts increased resistance to metal ion-dependent oxidation.

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