Interactions between cell death induced by statins and 7-ketocholesterol in rabbit aorta smooth muscle cells

摘要: 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 7-ketocholesterol exerted additive death effects. Experimental approach: Cultured rabbit aorta SMCs (passage 2–6) were exposed to with or without fluvastatin, simvastatin pravastatin. Uptake of neutral red (NR), monolayer protein, cleavage the pan-caspase substrate Asp-Glu-Val-Asp-rhodamine110, morphology (light electron microscopy) processing microtubule-associated protein 1 light chain 3 (LC3, immunoblot) determined. Key results: NR uptake declined upon 18 h exposure 25 μM (−41±3%, n=13), 100 μM fluvastatin (−59%) 30–100 μM (−28 −74%). Oxysterol high statin concentrations effects, but lower (fluvastatin 10–30 μM, 1–10 μM) partly reversed viability loss. 7-Ketocholesterol caused intense cytoplasmic vacuolization, LC3-I LC3-II, little caspase activation (increase 29.5%). Fluvastatin (10–100 μM, 70–545% increase) (3–100 μM 43–322% induced LC3 processing, failed activate caspases 7-ketocholesterol-treated SMCs. Pravastatin up was always inactive. Conclusions implications: 7-Ketocholesterol mainly via autophagic vesicle formation whereas lipophilic evoked Cell following low not additive, presumably because process interfered statin-induced activation. This further illustrates that drug effects normal are necessarily predictive for activities settings. British Journal Pharmacology (2008) 154, 1236–1246; doi:10.1038/bjp.2008.181; published online 12 May 2008