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Lysosomal destabilization during macrophage damage induced by cholesterol oxidation products
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
Department of Pathology, The Gade Institute, University of Bergen, Bergen, Norway.
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2000 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 28, no 2, 208-218 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2000. Vol. 28, no 2, 208-218 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-27688DOI: 10.1016/S0891-5849(99)00220-8Local ID: 12426OAI: oai:DiVA.org:liu-27688DiVA: diva2:248240
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Oxidized Lipids and Lysosomal Pathology in Atherogenesis
Open this publication in new window or tab >>Oxidized Lipids and Lysosomal Pathology in Atherogenesis
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Macrophages take up large amount of exogenous materials such as oxidatively modified low-density lipoproteins (oxLDL) and lysosomotropic agents. OxLDL is taken up into macrophage lysosomes through receptor-mediated endocytosis, but poorly degraded, resulting in foam cell formation. Cholesterol oxidation products, major toxic components of oxLDL, are involved in foam cell formation and the initiation of atherosclerosis. The production of ROS/RNS, cytokines, and matrix proteases by macrophages and the apoptosis of arterial cells may contribute to atherosclerotic plaque development and destabilization.

We had four objectives in this study, first we study the influence of oxLDL on lysosomal membrane stability, location and activity of lysosomal enzymes, macrophage cell death, and the modulation of these cellular characteristics by high-density lipoprotein (HDL), vitantin E (vit E), and the iron chelator desferrioximine (DFO) or iron complex. Second, we examined the role of lysosomal enzymes in macrophage apoptosis induced by oxysterols, the major cytotoxic components of oxLDL. Third, we analyzed the expression of cysteine protease cathepsins B and L and studied their relationship to macrophage apoptosis in human atherosclerotic lesions. And fourth, we investigated whether lysosomal rupture and release of lysosomal enzymes could initiate apoptosis using the lysosomotropic detergent MSDH.

The results suggest that oxLDL causes lysosomal destabilization and relocation of lysos'omal enzymes as indicated by increased cytosolic NABGase, cathepsin-L, and cathepsin D, and decreased lysosomal acridine orange (AO)-induced red fluorescence. AcLDL had no cytotoxic effects on the cells and their lysosomes. HDL, vit E, and the iron chelator DFO diminished the cytotoxicity of oxLDL by decreasing lysosomal damage, while the iron complex enhanced oxLDL cytotoxicity. Macrophage apoptosis induced by ChOx and 7-oxysterols (7B-OH and 7- keto) is associated with lysosomal rupture and release of lysosomal enzymes to the cytosol. The lysosomal punctuated immune-granularity of cathepsins B and L was decreased in 7 -oxysteroltreated cells compared to control cells. Moreover, there is enhancement and dispersion of cathepsins B and L immunoreactivity throughout 7-oxysterols-treated cells and an extensive immunoreaction in the nuclei and around nuclear areas of apoptotic cells. Using MSDH, a lysosomotropic detergent, we further demonstrated that lysosomal rupture and release of lytic enzymes indeed play an initial role in macrophage apoptosis.

There is a lesion dependent eo-expression of cathepsins B and Land caspase-3 in early and advanced human atherosclerotic lesions, which is associated with macrophage apoptosis.

We conclude that macrophage cell death including apoptosis induced by oxLDL and oxysterols is associated with lysosomal rupture and relocation of lysosomal hydrolytic enzymes to the cytosol. The released enzymes may initiate ceU death by activating the caspase cascade, attacking mitochondria, or directly attacking the nuclear of the cells. The high eo-expression of cathepsins B and L with caspase-3 in apoptotic macrophages in human atheroma lesions suggests that macrophage apoptosis and related hydrolytic enzymes may play an important role in lesion development and plaque instability.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2000. 56 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 652
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-28056 (URN)12819 (Local ID)91-7219-753-6 (ISBN)12819 (Archive number)12819 (OAI)
Public defence
2000-12-01, Berzeliussalen, Universitetssjukhuset, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-08-16Bibliographically approved

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Yuan, Xi MingLi, WeiBrunk, Ulf

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