title: Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering.
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 (n=20) contained 56+/-4 nmol total cholesterol/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 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.
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA. Carl_Sparrow@Merck.com
authors.forename: C P
authors.initials: CP
authors.lastname: Sparrow
authors.forename: C A
authors.initials: CA
authors.lastname: Burton
authors.forename: M
authors.initials: M
authors.lastname: Hernandez
authors.forename: S
authors.initials: S
authors.lastname: Mundt
authors.forename: H
authors.initials: H
authors.lastname: Hassing
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: R
authors.initials: R
authors.lastname: Rosa
authors.forename: A
authors.initials: A
authors.lastname: Hermanowski-Vosatka
authors.forename: P R
authors.initials: PR
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Peterson
authors.forename: P A
authors.initials: PA
authors.lastname: Detmers
authors.forename: Y S
authors.initials: YS
authors.lastname: Chao
authors.forename: S D
authors.initials: SD
authors.lastname: Wright
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D002351:Carrageenan / Q000008:administration & dosage; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006614:Hindlimb / Q000473:pathology; D007279:Injections, Subcutaneous; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019821:Simvastatin / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D008055:Lipids; D002351:Carrageenan; D002784:Cholesterol; D019821:Simvastatin