Document Detail

Lysosomal destabilization during macrophage damage induced by cholesterol oxidation products.
MedLine Citation:
PMID:  11281288     Owner:  NLM     Status:  MEDLINE    
We have previously shown that oxidized low-density lipoprotein (LDL) induces damage to the macrophage lysosomal membranes, with ensuing leakage of lysosomal contents and macrophage cell death. Cholesterol oxidation products (ChOx) have been reported to be the major cytotoxic components of oxidized LDL/LDL- and also to stimulate cholesterol accumulation in vascular cells. In the present study, we characterized the initial events during macrophage damage induced by cholesterol oxidation products (ChOx). Within 24 h of exposure, 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 pronounced 24 and 48 h after the exposure. Some lysosomal vacuoles were then filled with degraded cellular organelles, indicating phagocytosis of apoptotic bodies by surviving cells. Because caspase-3 activation was detected in the ChOx-exposed cells, lysosomal destabilization may associate with the leakage of lysosomal enzymes, and activation of the caspase cascade. MnSOD mRNA levels were markedly increased after 24 h of exposure to ChOx, suggesting associated induction of mitochondrial protection repair or turnover. We conclude that ChOx-induced damage to lysosomes and mitochondria are sequelae to the cascade of oxysterol cytotoxic events. The early disruption of lysosomes induced by ChOx, with resultant autophagocytosis may be a critical event in apoptosis and/or necrosis of macrophages/foam cells during the development of atherosclerotic lesions.
X M Yuan; W Li; U T Brunk; H Dalen; Y H Chang; A Sevanian
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Free radical biology & medicine     Volume:  28     ISSN:  0891-5849     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2000 Jan 
Date Detail:
Created Date:  2001-04-02     Completed Date:  2001-06-28     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  208-18     Citation Subset:  IM    
Division of Pathology II, Faculty of Health Sciences, Linköping University, Sweden.
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MeSH Terms
Apoptosis / drug effects
Autophagy / drug effects
Cathepsin D / metabolism
Cell Line
Cell Membrane Permeability / drug effects*
Cholesterol / analogs & derivatives*,  pharmacology*
Chromatin / drug effects,  ultrastructure
Cytosol / enzymology
Lysosomes / drug effects,  ultrastructure*
Macrophages / drug effects*,  ultrastructure
Superoxide Dismutase / genetics
Time Factors
Transcription, Genetic / drug effects
Grant Support
Reg. No./Substance:
0/Chromatin; 57-88-5/Cholesterol; EC Dismutase; EC D

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