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.

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.

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.

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