Objective-The objective of this study was to determine whether the potent selective cannabinoid receptor-1 antagonist rimonabant has antiatherosclerotic properties. Methods and Results-Rimonabant (50 mg/kg/d in the diet) significantly reduced food intake (from 3.35Ϯ.04 to 2.80Ϯ0.03 g/d), weight gain (from 14.6Ϯ0.7 g to Ϫ0.6Ϯ0.3 g), serum total cholesterol (from 8.39Ϯ0.54 to 5.32Ϯ0.18 g/L), and atherosclerotic lesion development in the aorta (from 1.7Ϯ0.22 to 0.21Ϯ0.037 mm 2 ) and aortic sinus (from 101 000Ϯ7800 to 27 000Ϯ2900 m 2 ) of LDLR Ϫ/Ϫ mice fed a Western-type diet for 3 months. Rimonabant also reduced plasma levels of the proinflammatory cytokines MCP-1 and IL12 by 85% (PϽ0.05) and 76% (PϽ0.05), respectively. Pair-fed animals had reduced weight gain (6.2Ϯ0.6 g gain), but developed atherosclerotic lesions which were as large as those of untreated animals, showing that the antiatherosclerotic effect of rimonabant is not related to reduced food intake. Interestingly, rimonabant at a lower dose (30 mg/kg/d in the diet) reduced atherosclerosis development in the aortic sinus (from 121 000Ϯ20 000 to 62 000Ϯ11 000 m 2 , 49% reduction, PϽ0.05), without affecting serum total cholesterol (7.8Ϯ0.7 g/L versus 8.1Ϯ1.3 g/L in the control group). Rimonabant decreased lipopolysaccharide (LPS)-and IL1␤-induced proinflammatory gene expression in mouse peritoneal macrophages in vitro as well as thioglycollateinduced recruitment of macrophages in vivo (10 mg/kg, po bolus). Conclusions-These results show that rimonabant has antiatherosclerotic effects in LDLRϪ/Ϫ mice. These effects are partly unrelated to serum cholesterol modulation and could be related to an antiinflammatory effect.

Recent data suggest that angiotensin II AT1 receptor antagonists may be beneficial in the treatment of atherosclerosis. To clarify how AT1 receptor antagonists reduce atherosclerosis, the effect of irbesartan on atherosclerotic lesion development was determined in low-fat, chow-fed apolipoprotein (Apo) E-deficient mice. Irbesartan (50 mg/kg per day) strongly decreased lesion development after a 12-week treatment period (lesion size: irbesartan treated, 20,524 +/- 4,200 microm(2) vs. control, 99,600 +/- 14,500; 79.4% inhibition, p < 0.001). This effect was not due to an effect of irbesartan on lipoprotein levels because irbesartan slightly increased total cholesterol levels and decreased the ratio of Apo A-I relative to Apo B levels. Immunochemical analysis of the atherosclerotic lesions using the mac3 monoclonal antibody showed the presence of macrophages in the lesions of control mice, whereas sections from irbesartan-treated animals only showed occasional labeling in the lesion area. These data suggest that irbesartan inhibits monocyte/macrophage influx into the vessel wall. Therefore, expression levels of monocyte chemoattractant protein-1 (MCP-1), as well as other chemokines involved in macrophage infiltration into the lesion area, were measured in the aortic sinus of control and irbesartan-treated animals. Irbesartan treatment strongly decreased MCP-1 mRNA levels as well as MCP-1 immunostaining in the lesion area. This effect of irbesartan on MCP-1 occurred without an effect on CCR2, the receptor of MCP-1. Expression of macrophage inflammatory protein (MIP)-1alpha, another CC chemokine expressed in atherosclerotic lesions, was also reduced after irbesartan treatment, without effect on CCR3 and CCR5, the receptors of MIP-1alpha. Concomitantly, the expression of the angiogenic chemokines KC and MIP-2, which are functionally related to interleukin-8, were downregulated, whereas their shared receptor CXCR2 was upregulated. These data suggest that inhibition of the inflammatory component of lesion progression plays an important role in the inhibitory effect of AT1 receptor antagonists on atherosclerotic lesion formation.