Lysosomal destabilization during macrophage damage induced by cholesterol oxidation products

We have previously shown that oxidized low-density lipoprotein (LDL) induce s damage to the macrophage lysosomal membranes, with ensuing leakage of lys osomal contents and macrophage cell death. Cholesterol oxidation products ( ChOx) have been reported to be the major cytotoxic components of oxidized L DL/LDL- and also to stimulate cholesterol accumulation in vascular cells. I n the present study, we characterized the initial events during macrophage damage induced by cholesterol oxidation products (ChOx). Within 24 h of exp osure, ChOx caused lysosomal destabilization, release to the cytosol of the lysosomal marker-enzyme cathepsin D, apoptosis, and postapoptotic necrosis . Enhanced autophagocytosis and chromatin margination was found 12 h after the exposure to ChOx, whereas apoptosis and postapoptotic necrosis was pron ounced 24 and 48 h after the exposure. Some lysosomal vacuoles were then fi lled with degraded cellular organelles, indicating phagocytosis of apoptoti c bodies by surviving cells. Because caspase-3 activation was detected in t he ChOx-exposed cells, lysosomal destabilization may associate with the lea kage of lysosomal enzymes, and activation of the caspase cascade. MnSOD mRN A levels were markedly increased after 24 h of exposure to ChOx, suggesting associated induction of mitochondrial protection repair or turnover. We co nclude that ChOx-induced damage to lysosomes and mitochondria are sequelae to the cascade of oxysterol cytotoxic events. The early disruption of lysos omes induced by ChOx, with resultant autophagocytosis may be a critical eve nt in apoptosis and/or necrosis of macrophages/foam cells during the develo pment of atherosclerotic lesions. (C) 2000 Elsevier Science Inc.