on August 25, 2003
Published online before print August 25, 2003, doi: 10.1161/01.CIR.0000086460.55494.AF
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Submitted on August 8, 2002
From Gaubius Laboratory, The Netherlands Organization for Applied Scientific Research (TNO)-Prevention and Health, Leiden, The Netherlands (R.K., H.M.G.P., J.J.E., T.K., L.M.H.); Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.W.J.); and Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.D.F., A.J.G.H.). * To whom correspondence should be addressed. E-mail: R.Kleemann{at}pg.tno.nl.
Background--Statins can exert anti-inflammatory antiatherosclerotic effects through an anti-inflammatory action, independent of lowering cholesterol. We addressed the question whether the anti-inflammatory activities of statins can reduce atherosclerosis beyond the reduction achieved by cholesterol lowering per se. Methods and Results--Two groups of 20 female APOE*3-Leiden mice received either a high-cholesterol diet (HC) or a high-cholesterol diet supplemented with 0.005% (wt/wt) rosuvastatin (HC+R). The HC diet alone resulted in a plasma cholesterol concentration of 18.9±1.4 mmol/L, and administration of rosuvastatin lowered plasma cholesterol to 14.1±0.7 mmol/L. In a separate low-cholesterol (LC) control group, the dietary cholesterol intake was reduced, which resulted in plasma cholesterol levels that were comparable to the HC+R group (13.4±0.8 mmol/L). Atherosclerosis in the aortic root area was quantified after 24 weeks. As compared with the HC group, the LC group had a 62% (P<0.001) reduction in cross-sectional lesion area. When compared with the LC group, the HC+R group showed a further decrease in cross-sectional lesion area (80%, P<0.001), size of individual lesions (63%, P<0.05), lesion number (58%, P<0.001), monocyte adherence (24%, P<0.05), and macrophage-containing area (60%, P<0.001). Furthermore, rosuvastatin specifically suppressed the expression of the inflammation parameters MCP-1 and TNF- Conclusions--Rosuvastatin reduces atherosclerosis beyond and independent of the reduction achieved by cholesterol lowering alone. This additional beneficial effect of rosuvastatin may be explained, at least partly, by its anti-inflammatory activity.
Revised on April 22, 2003
Accepted on May 9, 2003
Rosuvastatin Reduces Atherosclerosis Development Beyond and Independent of Its Plasma Cholesterol-Lowering Effect in APOE*3-Leiden Transgenic Mice. Evidence for Antiinflammatory Effects of Rosuvastatin
Robert Kleemann PhD*,
in the vessel wall and lowered plasma concentrations of serum amyloid A and fibrinogen, independent of its cholesterol-lowering effect.
Key words: atherosclerosis • inflammation • inhibitors • cholesterol • cell adhesion molecules
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