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We have examined the effect of zinc ions on low density lipoprotein (LDL) oxidation by macrophages, endothelial cells and iron ions in terms of the increased uptake of the LDL by macrophages. Zinc ions inhibited LDL modification by both cell types (which is dependent on the presence of iron ions in the culture medium) and by iron ions alone. As oxidised LDL is believed to be involved in atherogenesis, this raises the possibility that zinc may be an endogenous protective factor against atherosclerosis.

Oxidised low-density lipoprotein (LDL) produced by the action of arterial cells, including macrophages, has been implicated in atherosclerosis. We have investigated the effect of inhibitors of various cellular free-radical generating enzymes on macrophage-mediated LDL oxidation. Xanthine oxidase and nitric oxide synthase are not responsible for LDL modification by resident mouse peritoneal macrophages. Eicosatetraynoic acid, a lipoxygenase inhibitor, produced a dose-dependent irreversible inhibition of macrophage modification of LDL, but at concentrations rather close to those toxic to the cells. Diphenyl and diphenylene iodonium, NADPH oxidase and mitochondrial electron transport inhibitors, inhibited macrophage oxidation of LDL, at concentrations that were not obviously toxic. This suggests that NAPDH oxidase, or some other flavin nucleotide-dependent process, may be involved in LDL oxidation by macrophages. Wortmannin and thiopropionic acid dilauryl ester did not inhibit LDL oxidation, suggesting that inhibition of NADPH oxidase may not be the means by which the iodonium compounds inhibit LDL oxidation. Macrophages from C3H/HeJ mice, which lack receptors for lipopolysaccharide, modified LDL normally, suggesting that the inadvertent priming of resident macrophages by traces of lipopolysaccharide bound to LDL was not involved in LDL oxidation.

Oxidation of low density lipoprotein (LDL) in atherosclerotic lesions may be involved in converting macrophages into cholesterol-laden foam cells, a major characteristic of atherosclerotic lesions. It has been reported, and is widely believed, that endothelial cells derived from rabbit, pig and human aortas, but not those derived from bovine aortas, are capable of oxidising LDL in vitro. We have re-investigated this subject and found that during a 48-h incubation period bovine aortic endothelial cells (both in primary culture and in subcultures) were capable of consistently modifying LDL, increasing its uptake and degradation by macrophages by more than 4-fold. Incubation of LDL with bovine aortic endothelial cells for only 24 h, however, produced inconsistent modification of the LDL, whereas mouse peritoneal macrophages consistently modified LDL in 24 h. The modification of LDL by bovine aortic endothelial cells was an oxidative process, as the chain-breaking antioxidants, alpha-tocopherol and probucol, completely or greatly inhibited it. Thus, bovine aortic endothelial cells are capable of oxidising LDL but they are slower at doing so than are certain other types of cells. Nitric oxide generated by activated macrophages has very recently been shown to inhibit their oxidation of LDL. We have therefore investigated whether or not the inhibition of the constitutive nitric oxide synthase of bovine or porcine aortic endothelial cells would increase their rate of oxidation of LDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxidation of low density lipoprotein in atherosclerotic lesions may be involved in converting macrophages into lipid-laden foam cells. Lesions contain endothelial cells, smooth muscle cells, macrophages and lymphocytes. The first three types of cells have been shown previously to modify low density lipoprotein so as to increase its uptake by macrophages. We report here that lymphocytes from human blood are also capable of doing this. The modification process was an oxidative one because there was an increase in the thiobarbituric acid-reactive substances in media containing lymphocyte-modified low density lipoprotein and the modification could be inhibited by the antioxidants butylated hydroxytoluene and probucol. The lymphocyte-modified low density lipoprotein was taken up and degraded by macrophages by their scavenger receptor(s).