title: Fenofibrate reduces atherogenesis in ApoE*3Leiden mice: evidence for multiple antiatherogenic effects besides lowering plasma cholesterol.
abstract: OBJECTIVE
  To demonstrate, quantify, and mechanistically dissect antiatherosclerotic effects of fenofibrate besides lowering plasma cholesterol per se.
  
  
  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-kappaB 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Gaubius Laboratory, TNO-Pharma, P.O.Box 2215, 2301 CE Leiden, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Kooistra
authors.forename: L
authors.initials: L
authors.lastname: Verschuren
authors.forename: J
authors.initials: J
authors.lastname: de Vries-van der Weij
authors.forename: W
authors.initials: W
authors.lastname: Koenig
authors.forename: K
authors.initials: K
authors.lastname: Toet
authors.forename: H M G
authors.initials: HM
authors.lastname: Princen
authors.forename: R
authors.initials: R
authors.lastname: Kleemann
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001021:Aortic Valve / Q000473:pathology; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000097:blood* / Q000473:pathology*; D002784:Cholesterol / Q000097:blood*; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D000960:Hypolipidemic Agents; D008055:Lipids; D008074:Lipoproteins; C052720:apolipoprotein E3 (Leidein); D002784:Cholesterol; D011345:Fenofibrate