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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2322.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Fenofibrate Reduces Atherogenesis in ApoE*3Leiden Mice

Evidence for Multiple Antiatherogenic Effects Besides Lowering Plasma Cholesterol

T. Kooistra; L. Verschuren; J. de Vries-van der Weij; W. Koenig; K. Toet; H.M.G. Princen; R. Kleemann

From Gaubius Laboratory (T.K., L.V., J.d.V.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.

Correspondence to Robert Kleemann, PhD, Gaubius Laboratory, TNO-Pharma, P.O.Box 2215, 2301 CE Leiden, The Netherlands. E-mail R.Kleemann{at}pg.tno.nl or Robert.Kleemann@tno.nl

Objective— To demonstrate, quantify, and mechanistically dissect antiatherosclerotic effects of fenofibrate besides lowering plasma cholesterol per se.

Methods and Results— ApoE*3Leiden 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], soluble vascular cell adhesion molecule-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.

It is becoming increasingly clear that factors other than cholesterol determine atherogenesis. Using ApoE*3-Leiden mice, we demonstrate that fenofibrate, a PPAR-agonist, reduces atherosclerosis beyond the effect attributable to lowering total plasma cholesterol per se via mechanisms that may involve reduced vascular and systemic inflammation and increased macrophage cholesterol efflux.

Key Words: atherosclerosis • fibrates • inflammation • reverse cholesterol transport • pleiotrop

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