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Published on: November 10, 2017
Fenofibrate reduces atherogenesis in ApoE*3Leiden mice: evidence for multiple antiatherogenic effects besides
T Kooistra1, L Verschuren, J de Vries-van der Weij
1Gaubius Laboratory, TNO-Pharma, P.O.Box 2215, 2301 CE Leiden, The Netherlands.
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-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.
Insights
Fenofibrate significantly reduces atherosclerosis beyond its cholesterol-lowering effects. It also decreases inflammation and enhances cholesterol efflux, offering broader cardiovascular benefits.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Atherosclerosis Pathogenesis
Background:
- Atherosclerosis is a major cause of cardiovascular disease.
- Fenofibrate is a lipid-lowering drug with potential pleiotropic effects.
- Understanding fenofibrate's mechanisms beyond cholesterol reduction is crucial.
Purpose of the Study:
- To investigate the antiatherosclerotic effects of fenofibrate.
- To quantify fenofibrate's impact independent of plasma cholesterol levels.
- To elucidate the mechanistic pathways involved.
Main Methods:
- ApoE*3Leiden transgenic mice were fed high-cholesterol (HC) or HC with fenofibrate (HC+FF) diets.
- A low-cholesterol (LC) diet group controlled for plasma cholesterol levels.
- Atherosclerosis, inflammation markers, and gene expression were assessed.
Main Results:
- Fenofibrate significantly reduced atherosclerosis and aortic plaque load compared to diet-induced cholesterol lowering alone.
- Fenofibrate decreased aortic and systemic inflammation, including macrophage content and inflammatory mediators.
- Upregulation of apoE, ABC-A1, and SR-B1 suggested enhanced cholesterol efflux.
Conclusions:
- Fenofibrate exhibits antiatherosclerotic properties exceeding its lipid-lowering capacity.
- Reduced monocyte/macrophage recruitment and inflammation contribute to fenofibrate's benefits.
- Stimulation of cholesterol efflux pathways plays a role in fenofibrate's cardioprotective effects.
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