Publication
Title
Interactions between cell death induced by statins and 7-ketocholesterol in rabbit aorta smooth muscle cells
Author
Abstract
Background and purpose: 7-Ketocholesterol, an oxysterol present in atherosclerotic lesions, induces smooth muscle cell (SMC) death, thereby destabilizing plaques. Statins protect patients from myocardial infarction, though they induce SMC apoptosis. We investigated whether statins and 7-ketocholesterol exerted additive cell death effects. Experimental approach: Cultured rabbit aorta SMCs (passage 26) were exposed to 7-ketocholesterol with or without fluvastatin, simvastatin or pravastatin. Uptake of neutral red (NR), monolayer protein, cleavage of the pan-caspase substrate Asp-Glu-Val-Asp-rhodamine110, cell morphology (light and electron microscopy) and processing of microtubule-associated protein 1 light chain 3 (LC3, immunoblot) were determined. Key results: NR uptake declined upon 18 h exposure to 25 M 7-ketocholesterol (-413%, n=13), 100 M fluvastatin (-59%) or 30100 M simvastatin (-28 to -74%). Oxysterol and high statin concentrations exerted additive effects, but lower concentrations (fluvastatin 1030 M, simvastatin 110 M) partly reversed viability loss. 7-Ketocholesterol caused intense cytoplasmic vacuolization, processing of LC3-I to LC3-II, but little caspase activation (increase 29.5%). Fluvastatin (10100 M, 70545% increase) and simvastatin (3100 M 43322% increase) induced caspase activation without LC3 processing, but failed to activate caspases in 7-ketocholesterol-treated SMCs. Pravastatin up to 100 M was always inactive. Conclusions and implications: 7-Ketocholesterol caused SMC death, mainly via autophagic vesicle formation with LC3 processing, whereas lipophilic statins evoked SMC apoptosis. Cell death following 7-ketocholesterol and low statin concentrations were not additive, presumably because the autophagic process interfered with statin-induced caspase activation. This further illustrates that drug effects in normal SMCs are not necessarily predictive for activities in atherosclerotic settings.
Language
English
Source (journal)
British journal of pharmacology. - London
British journal of pharmacology. - London
Publication
London : 2008
ISSN
0007-1188
Volume/pages
154:6(2008), p. 1236-1246
ISI
000257613300008
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 16.10.2008
Last edited 17.06.2017
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