on July 27, 2006
Published online before print July 27, 2006, doi: 10.1161/01.ATV.0000238348.05028.14
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Submitted on January 9, 2006
Accepted on July 18, 2006
Fenofibrate Reduces Atherogenesis in ApoE*3Leiden Mice. Evidence for Multiple Antiatherogenic Effects Besides Lowering Plasma Cholesterol
T. Kooistra ;
From Gaubius Laboratory (T.K., L.V., J.v.d.W., K.T., H.M.G.P., R.K.), TNO-Pharma, Leiden, The Netherlands; University of Ulm (W.K.), Department of Internal Medicine II-Cardiology, Ulm, Germany; Leiden University Medical Center (L.V., R.K.), Department of Vascular Surgery, Leiden, The Netherlands.
* To whom correspondence should be addressed. E-mail: Robert.Kleemann{at}tno.nl.
Objective--To demonstrate, quantify, and mechanistically dissect antiatherosclerotic effects of fenofibrate besides lowering plasma cholesterol per se.
Methods and Results--ApoE*3-Leiden transgenic mice received either a high-cholesterol diet (HC) or HC containing fenofibrate (HC+FF) resulting in 52% plasma cholesterol-lowering. In a separate low-cholesterol diet (LC) control group, plasma cholesterol was adjusted to the level achieved in the HC+FF group. Low plasma cholesterol alone (assessed in LC) resulted in reduced atherosclerosis (lesion area, number and severity) and moderately decreased plasma serum amyloid-A (SAA) concentrations. Compared with LC, fenofibrate additively reduced lesion area, number and severity, and the total aortic plaque load. This additional effect in HC+FF was paralleled by an extra reduction of aortic inflammation (macrophage content; monocyte adhesion; intercellular adhesion molecule-1 (ICAM-1), sVCAM-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), MCP-1, and NF-
B expression), systemic inflammation (plasma SAA and fibrinogen levels), and by an upregulation of plasma apoE levels. Also, enhanced expression of ABC-A1 and SR-B1 in aortic macrophages may contribute to the antiatherosclerotic effect of fenofibrate by promoting cholesterol efflux.
Conclusion--Fenofibrate reduces atherosclerosis more than can be explained by lowering total plasma cholesterol per se. Impaired recruitment of monocytes/macrophages, reduced vascular and systemic inflammation, and stimulation of cholesterol efflux may all contribute to these beneficial effect of fenofibrate.
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