Inhibition of monocyte chemotactic protein-1 synthesis by statins.
The beneficial effects of statins on the reduction of cardiovascular events has been partly attributed to their anti-inflammatory properties. In the complex of the different pathogenetic events leading to atherosclerosis, recent data suggest a central role of monocyte chemotactic protein-1 (MCP-1), because mice knock-out for MCP-1 or its receptor CC-chemokine receptor 2 were considerably resistant to plaque formation. In this study we investigated the effect of different statins on in vitro and in vivo production of MCP-1. Lovastatin and simvastatin caused a dose-dependent inhibition of MCP-1 production in peripheral blood mononuclear cells exposed to lipopolysaccharide or inactivated Streptococcus hemoliticus and in human endothelial cells exposed to interleukin-1beta. The addition of mevalonate overrode the inhibitory effect of statins indicating that mevalonate-derived products are important for chemokine production. The in vivo anti-inflammatory effect of statins was investigated using the mouse air-pouch model of local inflammation. Lovastatin and pravastatin were orally administered to mice according to a treatment schedule that significantly inhibited the hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity without affecting total blood cholesterol. At the dose of 10 mg/kg, lovastatin and pravastatin reduced by approximately 50% the lipopolysaccharide-induced leukocytes recruitment and the exudate MCP-1 production. In conclusion, statins, by inhibiting mevalonate-derived products, reduced both in vitro and in vivo the production of chemokines involved in leukocyte migration, and this effect is unrelated to their cholesterol-lowering action.
Romano
M
M
Department of Molecular Biochemistry and Pharmacology, Istituto di Richerche Farmacologiche Mario Negri, Milan, Italy.
Diomede
L
L
Sironi
M
M
Massimiliano
L
L
Sottocorno
M
M
Polentarutti
N
N
Guglielmotti
A
A
Albani
D
D
Bruno
A
A
Fruscella
P
P
Salmona
M
M
Vecchi
A
A
Pinza
M
M
Mantovani
A
A
D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007962:Leukocytes / Q000502:physiology; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors; D009000:Monocytes / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000097:blood; D019821:Simvastatin / Q000494:pharmacology*
D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin; D008798:Mevalonic Acid