Human atherosclerotic lesions typically contain large amounts of
ferritin associated with apoptotic macrophages and foam cells, although the reasons are unknown. In the present investigation, we studied the relationship between
ferritin induction and occurrence of apoptosis in
7beta-hydroxycholesterol (7beta-OH)-treated monocytic cells and macrophages. We found that 7beta-OH enlarges the intracellular labile
iron pool, increases formation of
reactive oxygen species (ROS), and induces
ferritin and cytosolic accumulation of lipid droplets, lysosomal destabilization, and apoptototic macrophage death. Since
ferritin is a phase II-type protective
protein, our findings suggest that
ferritin upregulation here worked as an inefficient defense mechanism. Addition to the culture medium of both a membrane-permeable
iron chelator 10-phenanthroline and the non-membrane-permeable
iron chelators apoferritin and
desferrioxamine afforded significant protection against the 7beta-OH-induced effects. Consequently, endocytosed
iron compounds dramatically augmented 7beta-OH-induced cytotoxicity. We conclude that oxidized
lipid 7beta-OH causes not only foam cell formation but also oxidative damage with abnormal metabolism of cellular
iron. The findings suggest that modulation of
iron metabolism in human
atheroma may be a potential therapeutic strategy against
atherosclerosis.