Uptake by macrophages of low-density lipoprotein damaged by nitrogen dioxide in air

In order to know whether nitrogen dioxide, an environmental and endogenous free radical toxin, can participate in the formation of atherosclerotic lesions, damage to low-density lipoprotein (LDL) by nitrogen dioxide and uptake of the damaged LDL by macrophages were investigated. A solution of LDL at pH 7.5 was exposed to an atmosphere of nitrogen dioxide (70 ppm) in air at 37 degrees C for 5 or 10 h. Lipid oxidation was induced by the exposure as assessed by the formation of thiobarbituric acid reactive substances. Apolipoprotein B was covalently cross-linked via nondisulfide bonds. Fluorescence analysis showed that tryptophan residues were extensively decreased, and amino acid analysis indicated that the contents of histidine, lysine, and tyrosine residues were decreased by 30-40, 10-20, and 20-30%, respectively. Binding of LDL to thioglycolate-induced mouse peritoneal macrophages was markedly increased by the exposure as observed by the binding of mouse erythrocytes coated with LDL. The activity of LDL to convert macrophages into lipid-laden foam cells was also increased by the exposure. Modification of lysine residues of apo B with lipid oxidation products formed by the exposure may be responsible for the uptake by macrophages. The results suggest the possibility that exposure of LDL in vivo to nitrogen dioxide participates in the formation of atherosclerotic lesions.