Rimonabant, a Selective Cannabinoid CB1 Receptor Antagonist, Inhibits Atherosclerosis in LDL Receptor-Deficient Mice

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 3.35 +/- 04 to 2.80 +/- 0.03 g/d), weight gain (from 14.6 +/- 0.7 g to -0.6 +/- 0.3 g), serum total cholesterol (from 8.39 +/- 0.54 to 5.32 +/- 0.18 g/L), and atherosclerotic lesion development in the aorta (from 1.7 +/- 0.22 to 0.21 +/- 0.037 mm(2)) and aortic sinus (from 101 000 +/- 7800 to 27 000 +/- 2900 mu m(2)) of LDLR-/- mice fed a Western-type diet for 3 months. Rimonabant also reduced plasma levels of the proinflammatory cytokines MCP-1 and IL12 by 85% (P < 0.05) and 76% (P < 0.05), respectively. Pair-fed animals had reduced weight gain (6.2 +/- 0.6 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 121 000 +/- 20 000 to 62 000 +/- 11 000 mu m(2), 49% reduction, P < 0.05), without affecting serum total cholesterol (7.8 +/- 0.7 g/L versus 8.1 +/- 1.3 g/L in the control group). Rimonabant decreased lipopolysaccharide (LPS)- and IL1 beta-induced proinflammatory gene expression in mouse peritoneal macrophages in vitro as well as thioglycollate-induced recruitment of macrophages in vivo (10 mg/kg, po bolus). Conclusions-These results show that rimonabant has antiatherosclerotic effects in LDLR-/- mice. These effects are partly unrelated to serum cholesterol modulation and could be related to an antiinflammatory effect. (Arterioscler Thromb Vasc Biol. 2009; 29: 12-18.)