Novel modulators of atherogenesis: Insights from the endocannabinoid system

Atherosclerosis is a chronic inflammatory disease which is the primary cause of morbidity and mortality in the western world and whose identification of promising novel therapeutics is thus of great interest. The endocannabinoid system (ECS) comprises an ever-growing class of bioactive lipids known to exert numerous central and peripheral effects, including regulation of lipid metabolism, food intake and energy balance. Established evidences indicate that the ECS has been found to be activated in murine macrophages upon oxLDL and that type-1 cannabinoid receptor (CB1R) is considered as a risk factor in atherosclerosis since its activation promotes cholesterol accumulation and inflammatory mediators release. By contrast, recent evidences suggest a possible protective role for type-2 cannabinoid receptor (CB2R). However, the role of the whole ECS, which also comprises the endogenous ligands, the cannabinoid receptors and the enzymatic machinery responsible for endocannabinoids metabolism has yet to be thoroughly elucidated or understood in human atherosclerotic cells. Our data shows that several elements of the ECS are significantly altered in human foam cells and that the endogenous cannabinoids exert differential effects in regulating CD36-mediated intracellular oxLDL accumulation. Furthermore, we show an unprecedented effect of the ECS in modulating the inflammatory immune responses of human atherosclerotic cells via CB2R. Overall, we provide evidence that the ECS is indeed a novel biomarker of atherosclerosis and that is implicated in modulating several key hallmarks of this disease; thus our findings may be of crucial importance for the rational design of new endocannabinoid-based immunotherapeutic strategies for atherosclerosis or cardiovascular diseases.