Simvastatin Has Anti-Inflammatory and Antiatherosclerotic Activities Independent of Plasma Cholesterol Lowering

Abstract

Abstract-Inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, such as simvastatin, lower circulating cholesterol levels and prevent myocardial infarction. Several studies have shown an unexpected effect of HMG-CoA reductase inhibitors on inflammation. Here, we confirm that simvastatin is anti-inflammatory by using a classic model of inflammation: carrageenan-induced foot pad edema. Simvastatin administered orally to mice 1 hour before carrageenan injection significantly reduced the extent of edema. Simvastatin was comparable to indomethacin in this model. To determine whether the anti-inflammatory activity of simvastatin might affect atherogenesis, simvastatin was 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 cholesterol content. Aortas from control mice (nϭ20) contained 56Ϯ4 nmol total cholesterol/mg wet wt tissue, 38Ϯ2 nmol free cholesterol/mg, and 17Ϯ2 nmol cholesteryl ester/mg. Simvastatin (nϭ22) significantly (PϽ0.02) decreased these 3 parameters by 23%, 19%, and 34%, respectively. Histology of the atherosclerotic lesions showed that simvastatin did not dramatically alter lesion morphology. These data support the hypothesis that simvastatin has antiatherosclerotic activity beyond its plasma cholesterol-lowering activity.

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Effect of Intraperitoneally Injection of Different Doses of Lovastatin on Pain and Inflammatory Response Induced by Formalin in Mice

“…Studies demonstrate that simvastatin provides a highly effective therapy in treating murine Collagen-Induced Arthritis (CIA), a surrogate model for human Rheumatoid Arthritis (RA). Previous studies of thioglycolate peritonitis or carrageenan-induced paw pad inflammation suggested that statins modify acute inflammation (Sparrow et al, 2001;Weitz-Schmidt et al, 2001). Histological examination of paw lesions confirmed that simvastatin inhibits the acute inflammation induced by carrageenan.…”