on June 30, 2005
Published online before print June 30, 2005, doi: 10.1161/01.ATV.0000175756.56818.ee
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Submitted on January 28, 2005
Accepted on June 13, 2005
PPAR
, but not PPAR
, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia
Nathalie Hennuyer ;
From INSERM U545 (N.H., A.T., G.T., J.-C.F., B.S., C.F.), Département d’Athérosclérose, Institut Pasteur de Lille, France; Faculté de Pharmacie de Lille (A.T., J.-C.F., B.S.), Université de Lille 2, France; Laboratoire de Génétique Expérimentale (H.M.), Institut Pasteur de Lille, France.
* To whom correspondence should be addressed. E-mail: Catherine.Fievet{at}pasteur-lille.fr.
Objective--Peroxisome proliferator-activated receptor (PPAR) 
and 
are nuclear receptors that may modulate atherogenesis, not only by correcting metabolic disorders predisposing to atherosclerosis but also by directly acting at the level of the vascular wall. The accumulation of lipid-laden macrophages in the arterial wall is an early pivotal event participating in the initiation and promotion of atherosclerotic lesion formation. Because PPAR and modulate macrophage gene expression and cellular function, it has been suggested that their ligands may modulate atherosclerosis development via direct effects on macrophages. In this report, we investigated the effect of a PPAR ligand (fenofibrate) and 2 PPAR ligands (rosiglitazone and pioglitazone) on atherogenesis in a dyslipidemic nondiabetic murine model that develops essentially macrophage-laden lesions.
Methods and Results--Mice were fed a Western diet supplemented or not with fenofibrate (100 mpk), rosiglitazone (10 mpk), or pioglitazone (40 mpk) for 10 weeks. Atherosclerotic lesions together with metabolic parameters were measured after treatment. Fenofibrate treatment significantly improved lipoprotein metabolism toward a less atherogenic phenotype but did not affect insulin sensitivity. Contrarily, rosiglitazone and pioglitazone improved glucose homeostasis, whereas they did not improve lipoprotein metabolism. Fenofibrate treatment significantly decreased the accumulation of lipids and macrophages in the aortic sinus. However, surprisingly, neither rosiglitazone nor pioglitazone had an effect on lesion lipid accumulation or macrophage content.
Conclusion--These results indicate that in a dyslipidemic nondiabetic murine model, PPAR, but not PPAR, activators protect against macrophage foam cell formation.
Key words: atherosclerosis • foam cells • peroxisome proliferator-activated receptors
and •
ligands •
murine model
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