OxLDL-induced macrophage cytotoxicity is mediated by lysosomal rupture andmodified by intralysosomal redox-active iron

Oxidized low density lipoprotein (oxLDL) is believed to play a central role in atherogenesis. LDL. is oxidized in the arterial intima by mechanisms th at are still only partially understood. OxLDL is then taken up by macrophag es through scavenger receptor-mediated endocytosis, which then leads to cel lular damage, including apoptosis. The complex mechanisms by which oxLDL in duces cell injury are mostly unknown. This study has demonstrated that oxLD L-induced damage of macrophages is associated with iron-mediated intralysos omal oxidative reactions, which cause partial lysosomal rupture and ensuing apoptosis. This series of events can be prevented by pre-exposing cells to the iron-chelator, desferrioxamine (DFO), whereas it is augmented by pretr eating the cells with a low molecular weight iron complex. Since both DFO a nd the iron complex would be taken up by endocytosis, and thus directed to the lysosomal compartment, the results suggest that the normal contents of lysosomal low molecular weight iron may play an important role in oxLDL-ind uced cell damage, presumably by catalyzing intralysosomal fragmentation of lipid peroxides and the formation of toxic aldehydes and oxygen-centered ra dicals.