Rosuvastatin attenuates monocyte-endothelial cell interactions and vascular free radical production in hypercholesterolemic mice.
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.
Li
Wei
W
Division of Cardiovascular Medicine, Stanford University School of Medicine, CA 94305-5246, USA.
Asagami
Tomoko
T
Matsushita
Hidetsugu
H
Lee
Keun-Ho
KH
Tsao
Philip S
PS
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D005609:Free Radicals / Q000378:metabolism; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D005464:Fluorobenzenes; D005609:Free Radicals; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium