Abstract
One of the earliest observable events in atherogenesis is enhanced monocyte adhesion to the endothelium. In addition to reducing circulating levels of cholesterol, 3-hydroxy-3-methylglutaryl-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 apolipoprotein E-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, whereas showing little change in high-density lipoprotein cholesterol or triglycerides. Using a functional binding assay, we also demonstrated that endothelial adhesiveness for monocytes was significantly attenuated after 2 weeks of treatment with rosuvastatin. Quantitative real-time polymerase chain reaction determined that rosuvastatin reduced the expression of vascular cell adhesion molecule-1, monocyte chemotactic protein-1, and metalloproteinase-9 in the vessel wall. In addition, rosuvastatin inhibited vascular expression of p22phox 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.
Footnotes
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This work was supported by a grant from AstraZeneca.
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doi:10.1124/jpet.104.080002.
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ABBREVIATIONS: VCAM-1, vascular cell adhesion molecule-1; MCP-1, monocyte chemotactic protein-1; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low-density lipoprotein; NO, nitric oxide; eNOS, endothelial nitric-oxide synthase; apoE, apolipoprotein E; HBSS, Hanks' balanced salt solution; HDL, high-density lipoprotein; PG, prostaglandin; RT-PCR, real-time polymerase chain reaction; MMP, metalloproteinase; ROS, reactive oxygen species; TA, 4-amino-2,2,6,6,-tetramethylpiperidino-1-oxyl; CRP, C-reactive protein; NF-κB, nuclear factor of the κ-enhancer in B cells; PPAR, peroxisome proliferator-activated receptor.
- Received November 2, 2004.
- Accepted January 20, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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