Cholesterol secoaldehyde (3beta-hydroxy-5-oxo-5,6-secocholestan-6-al or ChSeco) is an
oxysterol known to be formed in reactions of
ozone with
cholesterol and also when cholesterol-5alpha-hydroperoxide undergoes Hock cleavage. In view of its widespread occurrence and atherogenic potential, we examined the effects of
ChSeco on mouse J774 macrophage viability and events associated with apoptosis. A dose-dependent decrease in cell viability, disruptions in mitochondrial transmembrane potential (64+/-5.5%; mean+/-SD, n=3), increased levels of cytosolic
cytochrome c (8.8+/-0.84 ng/ml; mean+/-SD, n=3), activation of
caspase-3 (ca. 3.6-fold) and
caspase-9 (ca.1.8-fold), and increased DNA fragmentation (ca. 5-fold), all indicative of apoptosis, were observed in response to exposure to
ChSeco. The apoptotic nature of cell death in macrophages was confirmed by dual staining with
acridine orange and
ethidium bromide. However, unlike the case with cardiomyoblasts and neuronal cells, the apoptotic process in these immune cells was not mediated by increased levels of
reactive oxygen species as indicated by a minimal or no increase in
2',7'-dichlorofluorescein fluorescence. It is suggested that the apoptotic process is mediated via the mitochondrial pathway and that
ChSeco formed in
biological environments contributes to the initiation, progression, and culmination of
atherosclerotic plaque formation, as these processes are critically dependent on macrophage apoptosis.