Published online before print August 25, 2003, doi: 10.1161/01.CIR.0000086460.55494.AF
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(Circulation. 2003;108:1368.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
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
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.).
Correspondence to Robert Kleemann, MD, Gaubius Laboratory, TNO-Prevention and Health, PO Box 2215, 2301 CE Leiden/the Netherlands. E-mail R.Kleemann{at}pg.tno.nl
Received August 8, 2002; de novo received February 7, 2003; revision received April 22, 2003; accepted May 9, 2003.
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-
in the vessel wall and lowered plasma concentrations of serum amyloid A and fibrinogen, independent of its cholesterol-lowering effect.
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.
Key Words: atherosclerosis • inflammation • inhibitors • cholesterol • cell adhesion molecules
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