Although the accumulation of
cholesterol and other lipidic material is unquestionably important in
atherogenesis, the reasons why this material progressively accumulates, rather than being effectively cleared by phagocytic cells such as macrophages, are not completely understood. We hypothesize that atheromatous lesions may represent "death zones" that contain toxic materials such as
oxysterols and in which monocytes/macrophages become dysfunctional and apoptotic. Indeed,
cathepsins B and L, normally confined to the lysosomal compartment, are present in the cytoplasm and nuclei of apoptotic (caspase-3-positive) macrophages within human
atheroma. The possible involvement of
oxysterols is suggested by experiments in which cultured U937 and THP-1 cells exposed to 7-oxysterols similarly undergo marked lysosomal destabilization,
caspase-3 activation, and apoptosis. Like macrophages within
atheroma, intralysosomal
cathepsins B and L are normally present in the cytoplasm and nuclei of these
oxysterol-exposed cells. Lysosomal destabilization,
cathepsin release, and apoptosis may be causally related, because inhibitors of
cathepsins B and L suppress
oxysterol-induced apoptosis. Thus, toxic materials such as 7-oxysterols in
atheroma may impair the clearance of
cholesterol and other lipidic material by fostering the apoptotic death of phagocytic cells, thereby contributing to further development of atherosclerotic lesions.