title: Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice.
abstract: Several clinical and angiographic intervention trials have shown that fibrate treatment leads to a reduction of the coronary events associated to atherosclerosis. Fibrates are ligands for peroxisome proliferator-activated receptor alpha (PPARalpha) that modulate risk factors related to atherosclerosis by acting at both systemic and vascular levels. Here, we investigated the effect of treatment with the PPARalpha agonist fenofibrate (FF) on the development of atherosclerotic lesions in apolipoprotein (apo) E-deficient mice and human apoA-I transgenic apoE-deficient (hapoA-I Tg x apoE-deficient) mice fed a Western diet. In apoE-deficient mice, plasma lipid levels were increased by FF treatment with no alteration in the cholesterol distribution profile. FF treatment did not reduce atherosclerotic lesion surface area in the aortic sinus of 5-month-old apoE-deficient mice. By contrast, FF treatment decreased total cholesterol and esterified cholesterol contents in descending aortas of these mice, an effect that was more pronounced in older mice exhibiting more advanced lesions. Furthermore, FF treatment reduced MCP-1 mRNA levels in the descending aortas of apoE-deficient mice, whereas ABCA-1 expression levels were maintained despite a significant reduction of aortic cholesterol content. In apoE-deficient mice expressing a human apoA-I transgene, FF increased human apoA-I plasma and hepatic mRNA levels without affecting plasma lipid levels. This increase in human apoA-I expression was accompanied by a significant reduction in the lesion surface area in the aortic sinus. These data indicate that the PPARalpha agonist fenofibrate reduces atherosclerosis in these animal models of atherosclerosis.
authors.affiliation: UR.545 INSERM-Institut Pasteur de Lille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Duez
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Melba
authors.initials: M
authors.lastname: Hernandez
authors.forename: Gérard
authors.initials: G
authors.lastname: Torpier
authors.forename: Philippe
authors.initials: P
authors.lastname: Poulain
authors.forename: Steven
authors.initials: S
authors.lastname: Mundt
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Teissier
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Burton
authors.forename: Alain
authors.initials: A
authors.lastname: Tedgui
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Fruchart
authors.forename: Catherine
authors.initials: C
authors.lastname: Fiévet
authors.forename: Sam D
authors.initials: SD
authors.lastname: Wright
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000502:physiology; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology; D001161:Arteriosclerosis / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D011345:Fenofibrate / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D014157:Transcription Factors / Q000819:agonists*; D014280:Triglycerides / Q000097:blood
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D002784:Cholesterol; D011345:Fenofibrate