Fenofibrate reduces atherogenesis in ApoE*3Leiden mice - Evidence for multiple antiatherogenic effects besides lowering plasma cholesterol

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-kappa B 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.