Published online before print October 9, 2008, doi: 10.1161/ATVBAHA.108.168757
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© 2009 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Rimonabant, a Selective Cannabinoid CB1 Receptor Antagonist, Inhibits Atherosclerosis in LDL Receptor–Deficient Mice
From Sanofi-Aventis R&D (F.D.-G., V.V., A.-M.M., P.S., F.B.), Toulouse, France; and Institut Pasteur de Lille, Département d’Athérosclérose (R.P., P.D., N.H., A.G., B.S.), INSERM U545,Université de Lille 2, Faculté de Pharmacie et de Médecine, Lille, France.
Correspondence to Françoise Bono, Sanofi-Aventis Recherche & Développement, Thrombosis & Angiogenesis Department, 195, Route d’Espagne, BP 13669, F-31036 Toulouse Cedex 1, France. E-mail francoise.bono{at}sanofi-aventis.com
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 mm2) and aortic sinus (from 101 000±7800 to 27 000±2900 µm2) 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 µm2, 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 IL1β-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.
Rimonabant (30 mg/kg/d in the diet) significantly reduced atherosclerotic lesion size in the aortic sinus of Western diet–fed LDLR-deficient mice without affecting serum cholesterol levels, whereas higher doses strongly decreased serum cholesterol and atherosclerosis. Rimonabant also reduced thioglycollate-induced recruitment of macrophages in vivo. These results show that rimonabant has antiatherosclerotic effects in LDLR–/– mice partly related to an antiinflammatory effect.
Key Words: atherosclerosis • rimonabant • obesity • LDLR-deficient mice
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