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J. Biol. Chem., Vol. 277, Issue 50, 48051-48057, December 13, 2002
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From the 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
Reduction of Atherosclerosis by the Peroxisome
Proliferator-activated Receptor
Agonist Fenofibrate in Mice*
,,,,
,,**
UR.545 INSERM-Institut Pasteur de Lille,
Lille 59019, France, § Merck Research Laboratories,
Rahway, New Jersey 07065, the Faculté de Pharmacie,
Université de Lille2, Lille 59006, France, and ¶ U.541
INSERM, Hôpital Lariboisière,
Paris 75475, France
(PPAR) that modulate risk factors related to atherosclerosis by acting at both systemic and
vascular levels. Here, we investigated the effect of treatment with the
PPAR 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 × 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 PPAR
agonist fenofibrate reduces atherosclerosis in these animal models of atherosclerosis.
*
This work was supported by grants from INSERM and
FEDER-Conseil Régional Nord Pas-de-Calais (Génopôle
01360124).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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