Background and Aims:
Recent development of endocannabinoid synthesis and degradation enzyme inhibitors may provide novel treatment modalities to combat metabolic and cardiovascular disorders. Here we provide proof-of-principle that inhibition of the ECS can be used to attenuate dyslipidemia and atherosclerosis in a mouse model for human-like lipoprotein metabolism.

Methods:
Female APOE*3-Leiden.CETP transgenic mice were fed a Western-type diet (containing 16% fat and 0.15% cholesterol) with or without supplementation of 0.017% w/w rimonabant for 20 weeks. Throughout the study, body composition was determined by echo-MRI, and plasma triglycerides (TG), total cholesterol and HDL-cholesterol (HDL-C) were measured in 4h fasted plasma samples. In the aortic valve region, atherosclerotic lesion severity was scored and atherosclerotic lesion area was quantified.

Results:
On average over the entire intervention period, rimonabant lowered fat mass (-1.0 g, p<0.01), plasma TG (-55%, p<0.001) and non-HDL-C levels (-17%, p<0.05), and increased plasma HDL-C levels (+52%, p<0.001). Importantly, rimonabant lowered severity of the atherosclerotic lesions (-50% severe lesions, p<0.05) and reduced overall atherosclerotic lesion area (-64%, p<0.01).

Conclusions:
In conclusion, rimonabant treatment of cholesterol-fed APOE*3-Leiden.CETP mice attenuates dyslipidemia and atherosclerosis, possibly via increased reverse cholesterol transport. We anticipate that modulating endocannabinoid synthesis and degradation enzymes provides a novel tool in the treatment of both metabolic and cardiovascular disorders.

04 - INHIBITION OF THE ENDOCANNABINOID SYSTEM ALLEVIATES DYSLIPIDEMIA AND ATTENUATES ATHEROSCLEROSIS DEVELOPMENT