Abstract 1364: Rimonabant, a Cannabinoid Receptor 1 Antagonist, Protects LDL Receptor Deficient Mice from Atherosclerosis.
Rimonabant is a potent CB1 receptor antagonist which has been shown to decrease body weight as well as a number of cardiometabolic risk factors in clinical trials carried out in overweight patients. These data are similar to results in mice which show that rimonabant decreases serum cholesterol and triglyceride levels in obese mice. We have now investigated whether these changes result in decreased atherosclerosis development in LDL receptor-deficient mice. These mice develop atherosclerotic lesions within 3 months when kept on Western-type diet (WD) containing 0.2 % cholesterol and 20 % fat. Three different groups of mice initially weighing 24.5 ±0.4 g were compared: (1) control group fed ad libitum with the WD, (2) Rimonabant-treated group (50mg/kg/d in the WD) and (3) pair-fed group, which was restricted to the same daily amount of food as the rimonabant-treated group. Whereas control mice weighed 39.1 ± 1.0 g after the three month treatment period, pair-fed mice weighed only 30.8 ± 0.6 g, and rimonabant-treated mice gained no weight (24.05 ±0.4 g). After three months of treatment, we observed that both control groups developed similar atherosclerosis lesions in the aorta and the aortic root, despite the differences in weight gain between these 2 groups. By contrast, a significant reduction of atherosclerotic lesions was observed in the entire aorta (>80% inhibition, p<0.001) and aortic sinus (71% decrease, p<0.01) of rimonabant-treated mice. This observation was correlated with a significant decrease in plasma total cholesterol (43% decrease, p<0.001) as well as LDL cholesterol (57% decrease, p<0.001) and triglyceride levels (56.8% decrease, p<0.01) in comparison to both control groups. We also observed a dramatic increase in serum monocyte chemotactic protein 1 (MCP1) levels in mice fed with WD (216 ±37.3 pg/ml in the “ad libitum” group and 236.5±46.1 pg/ml in the pair fed group ) in comparison with standard chow diet (28.1±3.2 pg/ml). The level of MCP1 in rimonabant treated mice was decreased to the level of the standard diet group (32.9 ± 7.1 pg/ml vs 28.1±3.2 pg/ml).These data suggest that rimonabant has specific anti-atherosclerotic effects, which are not related to its effect on food intake and could be related to an anti-inflammatory action of the compound.