Effects of Iron- and Hemoglobin-Loaded Human Monocyte–Derived Macrophages on Oxidation and Uptake of LDL

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Abstract
It is generally accepted that transition metals are required for cellular LDL oxidation. LDL may also be oxidized by iron and reducing agents in cell-free systems. We hypothesized that lysosomal iron may be exocytosed from macrophages that have been iron loaded by phagocytosis and degradation of iron-rich structures, eg, erythrocytes, and that such released iron may promote LDL oxidation and uptake by macrophages. Human monocyte–derived macrophages (HMDMs) were isolated and cultured for 7 days and then exposed to FeCl3, Fe-ADP, or Fe-EDTA (100 μmol/L) or hemoglobin (25 or 50 μg/mL) for 24 hours. After rinsing, LDL (50 to 150 μg/mL) was added in fresh culture medium without serum. After another 24 hours the media concentrations of iron and thiobarbituric acid–reacting substances as well as the electrophoretic mobility of LDL were increased, while the cells showed only minimal signs of decreased viability. Lipofuscin, neutral lipids, and phospholipids accumulated in a granular, lysosome-like pattern, and the cells acquired a foam cell–like morphology. There was a strong correlation (r=.87, P=.005) between the amount of iron added during the pre-exposure period and lipofuscin accumulation during the ensuing exposure to LDL in fresh, serum-free medium. Our results support our hypothesis and indicate that lysosomal iron may be exocytosed from HMDMs and promote oxidation and uptake of LDL and thus induce foam cell formation.