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• W1987777400 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 2–6) 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 μM 7-ketocholesterol (−41±3%, n=13), 100 μM fluvastatin (−59%) or 30–100 μM simvastatin (−28 to −74%). Oxysterol and high statin concentrations exerted additive effects, but lower concentrations (fluvastatin 10–30 μM, simvastatin 1–10 μM) 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 (10–100 μM, 70–545% increase) and simvastatin (3–100 μM 43–322% increase) induced caspase activation without LC3 processing, but failed to activate caspases in 7-ketocholesterol-treated SMCs. Pravastatin up to 100 μM 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. British Journal of Pharmacology (2008) 154, 1236–1246; doi:10.1038/bjp.2008.181; published online 12 May 2008" @default.
• W1987777400 created "2016-06-24" @default.
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• W1987777400 date "2008-07-01" @default.
• W1987777400 modified "2023-10-16" @default.
• W1987777400 title "Interactions between cell death induced by statins and 7-ketocholesterol in rabbit aorta smooth muscle cells" @default.
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• W1987777400 doi "https://doi.org/10.1038/bjp.2008.181" @default.
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