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Journal of Lipid Research, Vol 35, 385-398, Copyright © 1994 by Lipid Research, Inc.
M Aviram and M Rosenblat
Cells of the arterial wall including macrophages were shown to oxidize low
density lipoprotein (LDL) in vitro. Upon incubation of LDL with J- 774.A1
macrophage-like cell line for 18 h in the presence of 1 microM CuSO4,
extensive macrophage-mediated oxidation of the LDL fatty acids and
cholesterol moieties was demonstrated. Similar results were found with
mouse peritoneal macrophages or human monocyte-derived macrophages. Several
lines of evidence suggest that LDL binding to the LDL receptor on
macrophages is required for the cell-mediated oxidation of LDL. 1)
Incubation of the cells in the presence of monoclonal antibody to the LDL
receptor (IgG-C7), substantially inhibited lipoprotein oxidation. 2)
Pretreatment of LDL with monoclonal antibodies to the LDL receptor binding
domains on the LDL apoB-100 (mAbs B1B6 and B1B3) inhibited cell-mediated
oxidation of LDL by 52- 95%. 3) Down-regulation of the macrophage LDL
receptors (by preloading the cells with cholesterol) reduced LDL oxidation
by 42%. 4) Up- regulation of the LDL receptor (by macrophage incubation in
serum-free medium) was associated with 80% elevation in LDL oxidation. 5)
Macrophage activation with lipopolysaccharide up-regulated the LDL
receptors and was associated with up twofold increase LDL oxidation. 6)
Human monocyte-derived macrophages from a patient with homozygous familial
hypercholesterolemia, which lack the LDL receptor, failed to oxidize the
LDL. 7) On using acetylated LDL or methylated LDL, which do not bind to the
LDL receptor, macrophage-mediated oxidation of the lipoprotein did not
occur. The binding of LDL to the macrophage LDL receptor under oxidative
stress induced the oxidation of extracellular unbound LDL as demonstrated
by cell-mediated lipid peroxidation of mAb B1B6-treated LDL by cells that
were preincubated with native LDL. Furthermore, macrophage conditioned
medium (MCM) that was obtained after 5 h of cells preincubation with native
LDL under oxidative stress (1 microM CuSO4), followed by lipoprotein
removal and a further 18 h of cell incubation (but not MCM that was
similarly obtained without cell preincubation with LDL), was found to
contain oxidized linoleic and arachidonic acids and was able to induce LDL
lipids peroxidation. In conclusion, macrophage-mediated oxidation of LDL
requires an initial binding of the lipoprotein to the LDL receptor on the
cell surface under oxidative stress. This interaction leads to the
formation and release of cellular oxidized polyunsaturated fatty acids that
can oxidize the LDL molecule extracellularly.
ARTICLES
Macrophage-mediated oxidation of extracellular low density lipoprotein requires an initial binding of the lipoprotein to its receptor
Lipid Research Unit, Rambam Medical Center, Haifa, Israel.
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