Reduction of Atherosclerosis by the Peroxisome Proliferator-activated Receptor α 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 ␣ (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.

PPARα, but not PPARγ, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia

“…Previous studies from our 23 and other 27 laboratories have documented that PPAR␣ activation inhibits the development of atherosclerosis in apoE-deficient mice expressing a human apoA-I transgene, and LDL receptor-deficient mice, respectively. However, in both previous studies, it seemed that PPAR␣ ligands exert their antiatherosclerotic effects via mechanisms unrelated to their plasma lipid-lowering activity.…”

“…However, the development of a reliable experimental model is not easy, because, ideally, the regulatory pathways in the studied models need to be similar to those in humans. 28 Considering the different susceptibilities of mice strains to develop atherosclerosis, 29 considering the species differences in affinity of synthetic PPAR␣ agonists, 23,27 considering the species differences in regulatory pathways, testing hypolipidemic drugs in animal models may not necessarily generate predictive results for the human situation, but may even lead to erratic conclusions concerning their potential atheroprotective activities. 30 From this study, it seems that in contrast to other mouse models, E2-KI mice appear to be a relevant experimental model to test the efficacy of PPAR␣ agonists on dyslipidemia and atherosclerosis.…”

“…These doses were chosen based on their previously reported effects on atheroprotection or metabolic parameters in mice. 12,14,[22][23][24] The mice had ad libitum access to water and were weighed once per week. Blood was obtained after a 6-hour fasting period (8 AM to 2 PM) by retroorbital puncture under isoflurane-induced anesthesia or, depending on the analysis, by tail-cutting on conscious mice.…”

PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

“…Plaque growth depends on angiogenesis (33). Atherosclerosis is suppressed not only in PPAR␣ KO mice (34) but also in mice treated with fenofibrate (35). In more general terms, these counterintuitive results suggest a biphasic (U-shaped) doseresponse curve of host tissue to PPAR␣ activity, as is also observed with PPAR␥ agonists (29).…”

Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: Evidence for an antiinflammatory role for lipoprotein lipase

“…Many factors may have contributed to the phenotype of these ApoE Ϫ/Ϫ ͞PPAR␣ Ϫ/Ϫ mice: abnormal triglyceride metabolism in ApoE Ϫ/Ϫ , known interaction between ApoE and LPL (42), improved insulin sensitivity in PPAR␣ Ϫ/Ϫ mice (41), and͞or species-specific differences in PPAR␣ responses. Recently PPAR␣ agonist treatment was reported to decrease lesional cholesterol content in ApoE Ϫ/Ϫ mice, with a more pronounced effect in ApoE Ϫ/Ϫ mice expressing a human ApoA1 transgene (43). Cell-specific differences in PPAR␣ levels or LPL action may also influence atherosclerotic responses, for example, as seen in M (17).…”