Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering

Inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, such as simvastatin, lower circulating cholesterol levels and prevent myocardial in farction, Several studies have shown an unexpected effect of HMG-CoA reduct ase inhibitors on inflammation. Here, we confirm that simvastatin is anti-i nflammatory by using a classic model of inflammation: carrageenan-induced f oot pad edema. Simvastatin administered orally to mice 1 hour before carrag eenan injection significantly reduced the extent of edema. Simvastatin was comparable to indomethacin in this model. To determine whether the anti-inf lammatory activity of simvastatin might affect atherogenesis, simvastatin w as tested in mice deficient in apoE. Mice were dosed daily for 6 weeks with simvastatin (100 mg/kg body wt). Simvastatin did not alter plasma lipids. Atherosclerosis was quantified through the measurement of aortic cholestero l content. Aortas from control mice (n=20) contained 56+/-4 nmol total chol esterol/mg wet wt tissue, 38+/-2 nmol free cholesterol/mg, and 17+/-2 nmol cholesteryl ester/mg. Simvastatin (n=22) significantly (P<0.02) decreased t hese 3 parameters by 23%, 19%, and 34%, respectively. Histology of the athe rosclerotic lesions showed that simvastatin did not dramatically alter lesi on morphology, These data support the hypothesis that simvastatin has antia therosclerotic activity beyond its plasma cholesterol-lowering activity.