Fenofibrate reduces atherogenesis in ApoE*3Leiden mice: Evidence for multiple antiatherogenic effects besides lowering plasma cholesterol
article
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-κB 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. © 2006 American Heart Association, Inc. Chemicals / CAS: cholesterol, 57-88-5; fenofibrate, 49562-28-9; fibrinogen, 9001-32-5; intercellular adhesion molecule 1, 126547-89-5; Antilipemic Agents; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins E; Cholesterol, 57-88-5; Lipids; Lipoproteins; Procetofen, 49562-28-9
Topics
Biomedical ResearchAtherosclerosisFibratesInflammationPleiotropReverse cholesterol transportABC transporter A1CholesterolFenofibrateGranulocyte macrophage colony stimulating factorImmunoglobulin enhancer binding proteinIntercellular adhesion molecule 1Monocyte chemotactic protein 1Serum amyloid AVascular cell adhesion molecule 1Animal cellAnimal experimentAnimal modelAnimal tissueAorta atherosclerosisAtherogenesisCholesterol blood levelCholesterol dietCholesterol transportControlled studyDisease severityDrug effectMacrophageMouseNonhumanProtein blood levelProtein expressionTransgenic mouseUpregulationAnimalsAntilipemic AgentsAortaAortic ValveApolipoprotein E3Apolipoproteins EAtherosclerosisCholesterolFemaleInflammationLipidsLipoproteinsMiceMice, TransgenicProcetofen
TNO Identifier
239512
ISSN
10795642
Source
Arteriosclerosis, Thrombosis, and Vascular Biology, 26(10), pp. 2322-2330.
Pages
2322-2330
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