Lesion-derived low density lipoprotein and oxidized low density lipoprotein share a lability for aggregation, leading...

In this study we assessed whether low density lipoproteins (LDL) isolated from minced aortic atherosclerotic plaques obtained at autopsy (A-LDL) shared structural and functional properties with LDL oxidized by incubation with Cu2+ for 8-18 hours at 20 degrees C (Ox-LDL). Although both A-LDL and Ox-LDL represented monomeric particles about the size of LDL, both differed from LDL in that they showed an increase in electrophoretic mobility relative to LDL, an increase in cholesterol to protein ratio, and an increase in reactivity with a monoclonal antibody that recognizes epitopes on malondialdehyde (MDA)-modified proteins. In addition, both showed an increase in fluorescence at 360 nm excitation, 430 nm emission, an increase in fragmentation of apolipoprotein B with patterns that were quite similar, and an increase in recognition by the scavenger receptor on mouse peritoneal macrophages (MPMs) based on competition of 125I-A-LDL and 125I-Ox-LDL degradation by excess acetylated LDL. In addition, inhibition of degradation by MPMs of 125I-A-LDL and 125I-Ox-LDL by excess unlabeled Ox-LDL and A-LDL were similar. When MDA was added in increasing amounts to labeled LDL and A-LDL, less MDA was required to modify A-LDL than LDl to obtain ligands that were degraded by MPMs to the same degree. Finally, both A-LDL and Ox-LDL but not LDL underwent aggregation (increased metastability) when concentrated to levels exceeding 1 mg protein/ml and showed enhanced macrophage uptake via phagocytosis (inhibition by cytochalasin D). These results demonstrate that A-LDL and Ox-LDL share properties additional to those previously reported, suggesting that oxidation may be a major mode of modification of LDL accumulating in atherosclerotic lesions. This could lead to lipid loading of macrophages induced by phagocytosis of aggregated particles, in addition to unregulated uptake via the scavenger receptor of monomeric particles.