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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1897.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Nathalie Hennuyer; Anne Tailleux; Gérard Torpier; Hafid Mezdour; Jean-Charles Fruchart; Bart Staels; Catherine Fiévet

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.

Correspondence to Catherine Fiévet, INSERM U545, Département d’Athérosclerose, Institut Pasteur de Lille, 1 rue du Professeur Calmette, 59019 Lille cédex, France. E-mail Catherine.Fievet{at}pasteur-lille.fr

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
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.

In a dyslipidemic nondiabetic murine model characterized by macrophage-laden atherosclerotic lesions, we show that fenofibrate, but not rosiglitazone or pioglitazone, delays lesional lipid and macrophage accumulation.

Key Words: atherosclerosis • foam cells • peroxisome proliferator-activated receptors and • ligands • murine model

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors regulating the expression of genes that control lipid and glucose homeostasis, thus modulating the major metabolic disorders predisposing to atherosclerosis.¹ Moreover, PPARs exert additional antiinflammatory and lipid-modulating effects in the arterial wall, therefore being interesting molecular targets for the treatment of atherosclerosis.² PPARs are the targets of 2 classes of drugs currently used in clinical practice: fibrates (fenofibrate, clofibrate, ciprofibrate, and gemfibrozil) are PPAR agonists,

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whereas thiazolidinediones (TZDs) (rosiglitazone and pioglitazone) are potent PPAR activators.³ Although the beneficial effects of fibrate treatment on coronary events and atherogenesis in humans are well-documented through epidemiological and clinical intervention studies,^4–6 results of outcome trials with PPAR agonists in humans are still awaited to answer whether treatment with TZDs translates into a therapeutic benefit in atherosclerotic cardiovascular disease. The majority of clinical studies performed to date assessed the effects of TZDs in diabetic patients and most suggested vascular protective effects of PPAR ligands as determined by improved insulin-sensitivity, decreased vascular and systemic markers of inflammation, reduced carotid wall thickness and neointimal tissue proliferation, and, depending on the TZD, corrected dyslipoproteinemia.³ Interestingly, even in nondiabetic patients with coronary artery disease, rosiglitazone treatment induced beneficial effects on the vascular endothelium, exerted antiplatelet activity, and reduced carotid intima-media thickness progression.^7–10 All these reports argue for potent antiatherogenic effects of TZDs, raising the possibility of their use in clinical conditions other than diabetes. Consistent with this therapeutic potential of TZDs against atherosclerosis in humans, results from experimental animal studies showed that PPAR agonists reduce the development of atherosclerosis^11–15 and limit its complications.^16–20

In the present study, we investigated the effect of a PPAR ligand (fenofibrate) and 2 different PPAR ligands (rosiglitazone and pioglitazone) on atherogenesis in a dyslipidemic nondiabetic murine model that develops essentially macrophage-laden atherosclerotic lesions.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Animals and Diets
Homozygous human apolipoprotein (apo) E2 knock-in mice (E2-KI mice) were used in the study. These mice express human apoE2 instead of mouse apoE.²¹ At weaning, male mice were fed a Western diet containing (wt/wt) 0.2% cholesterol and 21% fat (UAR, Epinay sur Orge, France) supplemented or not (control group) with fenofibrate, rosiglitazone, or pioglitazone (n=10 per group) for 10 weeks. Based on food consumption monitoring, the daily drug delivery was 100, 10, and 40 mg/kg of body weight for fenofibrate, rosiglitazone, and pioglitazone, respectively. These doses were chosen based on their previously reported effects on atheroprotection or metabolic parameters in mice.^{12,14,22–24} 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. This study was conducted according to the Guidelines for the Care and Use of Experimental Animals.

Biochemical Analyses
At the end of the study, blood samples were drawn and glucose levels were determined using Glucotrend 2 (Roche Diagnostic, Meylan, France). Plasma was then separated for analyses. Insulin levels were determined using a solid phase 2-site enzyme immunoassay (Mercodia AB, Uppsala, Sweden). The homeostasis model of insulin resistance index was used as a measure of insulin resistance, in which homeostasis model of insulin resistance index=fasting plasma insulin (µU/mL) x fasting blood glucose (mmol/L)/22.5.²⁵ Plasma levels of total cholesterol (TC), triglycerides (TGs), and high-density lipoprotein (HDL) cholesterol (HDL-C) were measured using commercially available kits (Boehringer-Mannheim, Germany). Non-HDL cholesterol (N-HDL-C) was obtained by subtraction of HDL-C from TC. Lipoprotein cholesterol distribution profiles were analyzed in pooled plasma samples from each group by gel filtration chromatography using a Superose 6 HR 10/30 column (Amersham Pharmacia Biotech), as previously detailed.²⁶ Cholesterol concentration was determined in the eluted fractions as described.

Analysis of Atherosclerotic Lesions
After mice were euthanized by cervical dislocation, the heart of each animal was fixed with 4% phosphate-buffered paraformaldehyde (pH 7.0) and serial 10-µm-thick sections were cut between the valves and the aortic arch for quantitative analysis of lipid deposition by Oil red-O.²⁶ The sections were immunohistochemically stained with rat monoclonal anti-mouse macrophage (MOMA-2; Biosource International; 1:100 dilution) or mouse monoclonal anti–-actin antibodies (Sigma-Aldrich, France; 1:100 dilution) for smooth muscle cell (SMC) labeling, followed by detection with biotinylated secondary antibodies and streptavidin-horseradish peroxidase. Immunostains were visualized using the DAB substrate-chromogen system (DAKO Corporation, Carpinteria, Calif). Images were captured by use of a JVC 3-charge–coupled device video camera. Sections were analyzed using the computer-assisted Quips Image analysis system (Leica Mikroskopic und System GmbH, Wetzlar, Germany).

Statistical Analysis
Values are reported as mean±SD. The significance of differences between means was determined by ANOVA comparison of control and treated groups. Significant differences were then subjected to post-hoc analysis by using the Sheffe test. A value of P<0.05 was considered as statistically significant.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Male E2-KI mice were fed a Western diet with or without fenofibrate, rosiglitazone, or pioglitazone for 10 weeks. Both treated groups gained comparable weight as the control group, indicating that none of the compounds induced toxic effects (data not shown).

Fenofibrate, but not Rosiglitazone or Pioglitazone, Improves the Dyslipoproteinemia in E2-KI Mice
Compared with wild-type littermates, E2-KI mice fed a standard chow diet are dyslipidemic and display elevated plasma TC concentrations with low HDL-C/TC and high N-HDL-C/TC ratios, associated with increased TG levels (data not shown).

Fenofibrate-treated E2-KI mice exhibited a reduction in plasma TC concentrations (P<0.05). Both N-HDL-C (P<0.01) and TG (P<0.01) levels decreased, whereas HDL-C increased (P<0.001). In contrast, treatment with rosiglitazone or pioglitazone caused no significant changes in plasma lipid levels and only a slight decrease in both TG and TC (because of changes in N-HDL-C) levels were observed (Figure 1A). Analysis of the cholesterol distribution profiles (Figure 1B) confirmed the lipid results, demonstrating that fenofibrate strongly decreased the cholesterol-containing remnant lipoprotein particles (including very-low-density lipoproteins [VLDLs] and intermediary density lipoproteins [IDL]), and decreased low-density lipoproteins (LDLs). This effect was accompanied with a marked increase in HDL-C levels. By contrast, the cholesterol distribution profile of the rosiglitazone and pioglitazone groups was not really modified as compared with the control group, with only a slight increase in HDL-C in the pioglitazone group and a tendency for both TZDs to reduce remnant lipoprotein particle cholesterol content.

View larger version (18K): [in this window] [in a new window]   Figure 1. Fenofibrate, but not rosiglitazone or pioglitazone, improves the dyslipoproteinemia of E2-KI mice. A, Lipids were measured in E2-KI mice fed a Western diet (CON) supplemented with fenofibrate (FF), rosiglitazone (ROSI), or pioglitazone (PIO). Results are expressed as mean±SD. *P<0.05, **P<0.01, ***P<0.001 vs control group. B, Cholesterol was measured in lipoproteins separated by gel filtration chromatography from pooled plasma of E2-KI mice fed a Western diet (CON) (white circle) supplemented with fenofibrate (FF) (black triangle), rosiglitazone (ROSI) (white square), or pioglitazone (PIO) (black circle).

Rosiglitazone and Pioglitazone, but not Fenofibrate, Improve Glucose Homeostasis in E2-KI Mice
Chow-fed E2-KI mice present comparable fasting plasma glucose and insulin concentrations as compared with wild-type littermates suggesting unaltered glucose homeostasis and insulin-sensitivity in E2-KI mice (data not shown). These levels were unaffected by the Western diet and after 10 weeks, plasma glucose and insulin levels remained stable in the control group (135±19 versus 156±35 mg/dL for glucose; 0.490±0.217 versus 0.448±0.211 µg/L for insulin; means±SD, respectively, before and after diet).

Whereas no significant changes in fasting glucose or insulin levels were detected after fenofibrate treatment as compared with the control animals, a marked reduction in insulin levels (P<0.01) were observed in rosiglitazone- or pioglitazone-treated mice (Figure 2). Compared with control or fenofibrate-treated mice (5.49±0.08 and 5.69±0.16, respectively), rosiglitazone and pioglitazone also significantly reduced homeostasis model of insulin resistance index (3.15±0.21 and 3.74±0.03, respectively) (P<0.01).

View larger version (19K): [in this window] [in a new window]   Figure 2. Rosiglitazone and pioglitazone, but not fenofibrate, improve glucose homeostasis in E2-KI mice. Glucose and insulin levels in E2-KI mice fed a Western diet (CON) supplemented with fenofibrate (FF), rosiglitazone (ROSI), or pioglitazone (PIO). Results are expressed as mean±SD. **P<0.01 vs control group.

Fenofibrate, but not Rosiglitazone and Pioglitazone, Decreases Atherosclerosis Progression in E2-KI Mice
The effect of fenofibrate treatment on atherosclerosis was assessed in E2-KI mice by measuring oil-red-O–stained surfaces at the aortic sinus. Fenofibrate-treated mice showed significantly decreased atherosclerotic lesion surfaces (–90%) when compared with control mice (0.0140±0.0123 versus 0.0719±0.0189 mm²; P<0.001) (Figure 3A). In marked contrast, rosiglitazone and pioglitazone had no effect on atherosclerotic lesion size (0.0666±0.0229 and 0.0626±0.0257 mm², respectively) (Figure 3A).

View larger version (34K): [in this window] [in a new window]   Figure 3. Fenofibrate, but not rosiglitazone or pioglitazone, decreases atherosclerosis progression in E2- KI mice. A, Oil-red-O staining of atherosclerotic lesions in aortas of E2-KI mice fed a Western diet (CON) (white circle) supplemented with fenofibrate (FF) (black circle), rosiglitazone (ROSI) (white square), or pioglitazone (black square) (PIO). The graph shows atherosclerotic lesion surface area quantification. Each symbol represents the average area staining in 20 aortic sections from individual animals and the bar represents the median of the values. B, Representative photomicrographs showing atherosclerotic lesions in the aortic sinus of control (a, b) or mice treated with fenofibrate (c, d), rosiglitazone (e, f), or pioglitazone (g, h). In a, c, e, and g, the sections were stained with oil-red-O. b, d, f, and h, show staining with MOMA-2. Bar=0.5 mm

Representative photomicrographs of atherosclerotic lesions show a decrease of lipid-stained surfaces at the aortic sinus from fenofibrate-treated E2-KI mice as compared with control or rosiglitazone or pioglitazone-treated animals (Figure 3B, a, c, e, g). Moreover, as revealed by MOMA-2–specific staining of the lesions (Figure 3B, b, d, f, h), macrophages colocalized with oil-red-O–stained-areas, pointing to a critical role for macrophages in atherogenesis on the E2-KI mice. Interestingly, rosiglitazone or pioglitazone treatment did not lead to altered macrophage content within the atherosclerotic lesions. In contrast, few SMCs were present in the atherosclerotic lesions of E2-KI mice and SMC staining was not different between control and treated mice.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In a nondiabetic murine model (E2-KI mice) that displays mixed dyslipidemia and develops atherosclerotic lesions consisting mainly of foam cells, we report that PPAR activators have no effect on the promotion of atherogenesis. Conversely, a PPAR ligand delays the development of atherosclerosis in the mice.

Atherosclerosis results from a cascade of events that involve interactions between the vessel wall and blood components. The atherosclerotic lesion development starts as a result of endothelial injury and dysfunction triggered by risk factors for atherosclerosis. This injury facilitates recruitment of circulating lipoproteins into the artery wall, which are oxidized and consequently induce a chronic inflammatory response characterized by the appearance of peripheral blood cells, including monocytes. The local production of chemokines further attracts and enhances migration of the monocyte/macrophages into the vascular wall which then engulf the oxidized lipoprotein particles and transform into foam cells, constituting as such the fatty streaks. Foam cell formation is accompanied by macrophage activation characterized by induced expression of genes coding for inflammatory cytokines and growth factors. These growth factors cause smooth muscle cells to migrate from the media into the intima, where they proliferate, resulting in intimal hyperplasia and formation of fibroproliferative lesions, characteristic of advanced atherosclerotic plaques. Thrombotic occlusion caused by deposition of platelets and clot formation may ensue, leading, finally, in cases of rupture, to clinical events such as myocardial infarction or stroke.

Previous studies from our²³ and other²⁷ 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. This observation is in line with a number of clinical studies reporting that the inhibition of atheromatous plaque progression as well as the decreased incidence of cardiovascular events on fibrate treatment occurs via effects possibly independent or in addition to their systemic action.^5,6 Nevertheless, it is well known that controlling metabolic risk factors for atherosclerosis, such as dyslipidemia, improves endothelial dysfunction, an early pivotal event in the atherosclerosis process. It is interesting to point out that the beneficial effects of fenofibrate on lipid and lipoprotein metabolism in the E2-KI mice in the present study most likely participate in the favorable effect of the drug on atherosclerosis. Fenofibrate treatment decreased the atherogenic lipoprotein particles (VLDL, IDL, and LDL), and increased the protective HDL levels. The preclinical development of PPAR agonists, which would be expected to act on lipid metabolism and hence atherosclerosis, includes the analysis of their effects in appropriate murine models. 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.

Unexpectedly, our results demonstrate that treatment with 2 different PPAR ligands do not protect E2-KI mice from atherosclerosis and foam cell accumulation. Previous studies performed in different mouse models (LDL receptor-deficient or apoE-deficient mice) demonstrated an atheroprotective effect of PPAR activation by TZDs.^11–15 From these studies, it could be plausibly concluded that the overall beneficial action of the TZDs occurred independently from systemic lipid changes and, possibly, from the insulin sensitizer activity of the compounds.^12,13,15 In our present study, no significant changes in lipoprotein metabolism were observed in rosiglitazone-treated or pioglitazone-treated mice, and although glucose homeostasis was improved in the mice, this improvement was not sufficient to induce a delay in atherosclerosis development in this mouse model with normal glucose homeostasis. It is interesting to remark that at the doses used in our study, pioglitazone has no hypolipidemic effect. Because E2-KI mice respond well to PPAR agonists, it appears that unlike suggested by in vitro experiments,^31,32 pioglitazone exerts very little if any PPAR activity, at least under the experimental conditions tested here.

PPAR and PPAR are expressed in all cell types of the arterial wall, including endothelial cells, monocytes/macrophages, and vascular SMCs.² Potentially direct antiatherosclerotic parietal effects of PPAR agonists have been observed in in vitro experiments, in vivo animal studies, as well as in clinical studies in humans.^2,33 Besides their activities on macrophage lipid homeostasis with direct consequences for atherosclerosis development,³⁴ PPAR and PPAR modulate the earliest step of the atherosclerotic lesion by inhibiting the expression of certain cytokines involved in the recruitment of monocytes/macrophages by endothelial cells.^27,35–37 Through these properties, PPAR and PPAR may exert cardiopreventive activities by decreasing foam cell formation. Our results show that PPAR activation has a beneficial effect on lipid-laden macrophage accumulation in the aortic sinus and it is plausible that the pleiotropic action of fenofibrate has contributed together with its hypolipidemic activity to the atheroprotective benefit seen in the mice. By contrast, the lack of effect of PPAR activation on macrophage accumulation in mice contrasts with previous in vivo animal studies showing protective effects.^11–15 Although the exact reasons are unclear, several explanation can be evoked. Atherosclerosis in the E2-KI mice, in contrast to other mouse models, is characterized by the almost exclusive presence of macrophages. It is possible that in the context of severe, uncorrected dyslipidemia, PPAR activation in macrophages is insufficient to reverse the pro-atherogenic program. Moreover, a substantial controversy exists on the role of PPAR in macrophage cholesterol metabolism in mice. In vitro, PPAR ligands may induce macrophage foam cell formation through CD36 induction and increased uptake of oxidized LDL.³⁸ However, in vivo rosiglitazone treatment in obese insulin-resistant ob/ob mice resulted in a decrease of peritoneal macrophage CD36 protein content likely caused by the insulin-sensitizing activity of the compound.³⁹ However, LDL receptor-deficient mice that display only mild insulin resistance showed an increase in CD36 protein after rosiglitazone treatment in vivo. The effects of rosiglitazone on foam cell formation and atherogenesis could therefore differ depending on the degree of insulin resistance. E2-KI mice are nondiabetic and are not insulin resistant; therefore, the impact of PPAR agonists on macrophages may not be sufficient to improve atherosclerosis in this mouse model. Thus, whether these observations can be extended to the human situation is unclear. Previous results on human and murine macrophages has demonstrated significant species differences in the control of cholesterol homeostasis by PPAR ligands.^27,34 For instance, whereas PPAR activation results in the induction of the cholesterol efflux transporter ABCA1 in human macrophages,³⁴ this effect is much less pronounced in murine macrophages.²⁷ Finally, it is possible that the atheroprotective effects of PPAR are mediated via other cell types that do not participate in E2-KI mice atherogenesis such as SMCs. In this respect, it is interesting to note that TZD treatment has been shown to improve endothelial function and decrease intima-media thickness also in nondiabetic patients.^7–10 Such activities may be mediated, in part, via their effects on the proliferation and migration of vascular SMCs and the antiinflammatory activities in these and other cell types involved in atherogenesis.^40–46 Moreover, PPAR and PPAR ligands may influence thrombogenesis and inhibit proteins implicated in plaque rupture resulting in plaque stabilization.^{18–20,47–49} Unfortunately, no murine models are currently available to test such effects.⁵⁰ Therefore, we cannot exclude that determining the effects of TZDs on advanced atherosclerosis may prove to be a stronger predictor of their potential clinical benefit and testing their effects in other atherosclerosis models and in humans is therefore warranted.

	Acknowledgments

 
This work was supported in part by grants of the Feder Conseil Régional Nord-Pas de Calais (Génopole 01360124), the Leducq Foundation, and Consortium 02 2 0475. Technical assistance by Jonathan Vanhoutte and Emmanuel Bouchaert is kindly acknowledged.

Received January 28, 2005; accepted June 13, 2005.

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