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Rosuvastatin attenuates monocyte-endothelial cell interactions and vascular free radical production in
Wei Li1, Tomoko Asagami, Hidetsugu Matsushita
1Division of Cardiovascular Medicine, Stanford University School of Medicine, CA 94305-5246, USA.
Insights
Rosuvastatin treatment significantly reduced monocyte adhesion to blood vessel walls in mice. This anti-inflammatory effect, observed early in atherogenesis, suggests rosuvastatin offers vascular benefits beyond cholesterol reduction.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Immunology
Background:
- Atherogenesis involves early monocyte adhesion to the endothelium.
- Statins, like rosuvastatin, may possess direct vascular anti-inflammatory effects.
- Apolipoprotein E-deficient mice are a model for studying atherosclerosis.
Purpose of the Study:
- To investigate the anti-inflammatory effects of rosuvastatin on the vessel wall.
- To determine if rosuvastatin reduces endothelial monocyte adhesion.
- To assess rosuvastatin's impact on inflammatory markers in vivo.
Main Methods:
- Atherosclerosis model using apolipoprotein E-deficient mice.
- Subcutaneous administration of rosuvastatin (0-20 mg/kg) or vehicle for 2 or 6 weeks.
- Assessment of plasma lipids, endothelial cell adhesion assays, and gene/protein expression analysis (VCAM-1, MCP-1, MMP-9, p22phox, superoxide, 8-isoprostanes).
Main Results:
- Rosuvastatin lowered plasma total cholesterol without significantly altering HDL or triglycerides.
- Endothelial adhesiveness for monocytes was significantly reduced after 2 weeks of rosuvastatin treatment.
- Rosuvastatin decreased expression of VCAM-1, MCP-1, MMP-9, p22phox, and reduced superoxide production and plasma 8-isoprostanes.
Conclusions:
- Rosuvastatin exhibits acute anti-inflammatory actions on the vessel wall.
- These anti-inflammatory effects likely contribute to the beneficial actions of rosuvastatin in atherogenesis.
- Early intervention with rosuvastatin may mitigate inflammatory processes involved in atherosclerosis development.
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 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.
