Vitamin C prevents metal ion-dependent initiation and propagation of lipid peroxidation in human low-density lipoprotein.
Lipid peroxidation and oxidative modification of low-density lipoprotein (LDL) have been implicated as causal factors in the pathogenesis of atherosclerosis, and prevention of LDL oxidation by antioxidants may be an effective strategy to inhibit the progression of the disease. We investigated the effects of the reduced form of vitamin C (L-ascorbic acid, AA) and its two-electron oxidation product (dehydro-L-ascorbic acid, DHA) upon metal ion-dependent oxidative modification of human LDL. We found that low micromolar concentrations of both AA and DHA protect LDL against oxidation induced by Cu2+ or by hemin and hydrogen peroxide. In a dose-dependent manner, AA and DHA prevented the initiation of lipid peroxidation in LDL, as determined by a sensitive and selective assay for lipid hydroperoxides utilizing HPLC with chemiluminescence detection. AA and DHA also preserved the LDL-associated antioxidants alpha-tocopherol, beta-carotene, and lycopene, but not ubiquinol-10. Furthermore, AA was able to stop propagation of lipid peroxidation in LDL, whereas DHA lacked this ability. The addition of 60 microM AA to LDL containing up to 38 nmol/mg protein of pre-formed lipid hydroperoxides led to their rapid disappearance; this activity of AA was dependent on the presence of redox-active copper, but did not lead to the formation of lipid hydroxides, the reduced form of lipid hydroperoxides. Our data show that in Cu(2+)-exposed LDL (i) vitamin C primarily spares, rather than regenerates, alpha-tocopherol and other endogenous antioxidants, except for AA and DHA prevent initiation of lipid peroxidation in LDL; and (iii) AA can terminate lipid peroxidation, thereby protecting partially oxidized LDL against further oxidative modification.
Retsky
K L
KL
Whitaker Cardiovascular Institute, Boston University School of Medicine, MA, USA.
Frei
B
B
D000328:Adult; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology*; D002788:Cholesterol Esters / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000494:pharmacology; D003683:Dehydroascorbic Acid / Q000494:pharmacology*; D004587:Electrophoresis, Agar Gel; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008054:Lipid Peroxides / Q000032:analysis; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism*; D008163:Luminescent Measurements; D004369:Pentetic Acid / Q000494:pharmacology
D000975:Antioxidants; D002788:Cholesterol Esters; D005609:Free Radicals; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; D006427:Hemin; D003300:Copper; D004369:Pentetic Acid; D006861:Hydrogen Peroxide; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid