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. 2001 Feb 27;98(5):2610-5.
doi: 10.1073/pnas.041609298. Epub 2001 Feb 20.

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

T Claudel  1 , M D Leibowitz, C Fiévet, A Tailleux, B Wagner, J J Repa, G Torpier, J M Lobaccaro, J R Paterniti, D J Mangelsdorf, R A Heyman, J Auwerx
Affiliations

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

T Claudel et al. Proc Natl Acad Sci U S A. .

Abstract

A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. Dysregulation of such metabolic pathways can lead to the development of atherosclerosis, a disease influenced by both systemic and local factors. Here we analyzed the effects of activation of RXR and some of its heterodimers in apolipoprotein E -/- mice, a well established animal model of atherosclerosis. An RXR agonist drastically reduced the development of atherosclerosis. In addition, a ligand for the peroxisome proliferator-activated receptor (PPAR)gamma and a dual agonist of both PPARalpha and PPARgamma had moderate inhibitory effects. Both RXR and liver X receptor (LXR) agonists induced ATP-binding cassette protein 1 (ABC-1) expression and stimulated ABC-1-mediated cholesterol efflux from macrophages from wild-type, but not from LXRalpha and beta double -/-, mice. Hence, activation of ABC-1-mediated cholesterol efflux by the RXR/LXR heterodimer might contribute to the beneficial effects of rexinoids on atherosclerosis and warrant further evaluation of RXR/LXR agonists in prevention and treatment of atherosclerosis.

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Figures

Figure 1
Figure 1
Area affected by atherosclerotic lesions in the heart outflow tract of apoE −/− mice. (A) Different groups of 15 animals each were treated with a PPARγ agonist, a PPARα/γ coagonist, or a rexinoid. Lesion area was determined as specified in Experimental Procedures. Results are expressed as the mean ± SD. Significance levels (Student's t test) are represented by asterisks (*, P < 0.05; *, *, P < 0.01; *, *, *, P < 0.001). (B) Lesion size as a function of distance to the aortic valves in apoE −/− mice treated as specified in A. Serial sections were cut from the heart valves to the aortic crosses and stained and analyzed as specified. Each point corresponds to the mean surface of lesions measured for the 15 mice in each group at a given distance from the valves. The corresponding standard deviations are not shown, to improve the clarity of the graphic. (C) Representative photographs of atherosclerosis in the aorta of apoE −/− mice, a relevant section from an untreated apoE −/− mouse (control), and an equivalent section of an apoE-deficient mouse after receiving GW2331 (PPARα/γ coagonist) or LG100364 (RXR agonist).
Figure 2
Figure 2
Changes in lipid (A), apolipoprotein (B), and glucose (C) metabolism by the various treatments in apoE −/− animals. (A) Cholesterol and triglyceride levels in apoE −/− animals treated with either a PPARγ agonist, a PPARα/γ coagonist, or a rexinoid. Results are expressed as mean ± SD. Significant differences by Student's t test are indicated by asterisks. (B) Serum levels of the different apolipoproteins in apoE −/− mice subjected to the different treatments. Values are expressed as a percentage of the value in the control group, and significant differences are indicated. (C) Fasting serum glucose and insulin levels in apoE −/− mice. Results are expressed as mean ± SD. No significant differences between the groups existed. (D) Representative lipoprotein profiles obtained after size exclusion chromatography of pooled serum of three control apoE −/− animals (open symbols) and of three apoE −/− mice receiving a PPARγ agonist, a PPARα/γ coagonist, or a rexinoid (black closed symbols). Cholesterol was determined in the various fractions. The elution of very LDL and HDL in normal mouse serum is indicated in italics (Bottom).
Figure 3
Figure 3
Ligands for RXR and LXR induce macrophage ABC-1 expression and cholesterol efflux. (A) ABC-1 mRNA levels in RAW 264.7 cells treated for 24 h with either a ligand for LXRα [22(R)-OH-Cholesterol; 10 μM] or a rexinoid (LG101305; 1 μM). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a control probe. Relative fold induction of ABC-1 mRNA after normalization to the GAPDH expression is indicated under the blots. (B) ApoA-I-mediated cholesterol efflux in peritoneal macrophages obtained from control mice. Macrophages were treated with the agonists as specified under A. In addition to these treatments, macrophages were also challenged with a PPARγ agonist (BRL 49,653; 10 μM). (C) ApoA-I-mediated cholesterol efflux in peritoneal macrophages from LXRα and β double −/− mice.
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