Received for publication November 4, 2004.
Revised January 19, 2005.
Accepted for publication January 20, 2005.

Rosuvastatin Attenuates Monocyte-Endothelial Cell Interactions and Vascular Free Radical Production in Hypercholesterolemic Mice

Abstract

One of the earliest observable events in atherogenesis is enhanced monocyte adhesion to the endothelium. In addition to reducing circulating levels of cholesterol, HMG-CoA reductase inhibitors (statins) are thought to have direct salutary effects upon vascular cells. We hypothesized that the new statin, rosuvastatin, would have anti-inflammatory effects on the vessel wall. Eight-week old apoE-deficient mice were fed a normal chow diet for a period of 12 weeks. During this time mice were administered vehicle or rosuvastatin at a dose of 0, 1, 5, or 20 mg/kg by subcutaneous injection at the same time daily for a period of 2 or 6 weeks prior to sacrifice. At the end of the study, rosuvastatin-treated animals displayed lower plasma total cholesterol levels while showing little change in HDL cholesterol or triglycerides. Using a functional binding assay, we also demonstrated that endothelial adhesiveness for monocytes was significantly attenuated after two weeks of treatment with rosuvastatin. Real-time rt-PCR determined that rosuvastatin reduced the expression of VCAM-1, MCP-1, and metalloproteinase (MMP)-9 in the vessel wall. In addition, rosuvastatin inhibited vascular expression of p22^phox and superoxide production, as well as diminishing plasma 8-isoprostanes concentrations. Thus, treatment with rosuvastatin has acute anti-inflammatory actions that likely participate in its beneficial actions during atherogenesis.

Key words: adhesion molecule, atherosclerosis, chemokine, endothelium, statin, superoxide anion

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