Endocannabinoids and atherosclerosis: the future of therapeutic strategies—a review

Abstract

The endocannabinoid system (ECS) is a widespread cell signaling system in the human body, composed of the endocannabinoid molecules-anandamide, 2-arachidonoyl glycerol, their primary receptors, and the associated enzymes responsible for synthesis and degradation. Together, these components of the ECS work harmoniously to maintain homeostasis. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, with atherosclerosis as the principal risk factor. Atherosclerosis is a progressive disease characterized by the formation of lipid-rich plaques within the walls of medium and large vessel arteries. This process begins with endothelial damage and, progresses through a cascade of events, including lipid accumulation, fibrosis, and calcification, that leads to vessel narrowing and inflammation. The resulting atheromatous plaque, along with complications such as rupture, thrombosis, or embolism contributes to serious cardiovascular outcomes. The role of endocannabinoids in cardiovascular pathology, particularly through the cannabinoid (CB) 1 and 2 receptors has gained attention. Studies have shown that CB1 receptors are pro-atherogenic while CB2 receptors exhibit anti-atherogenic properties. Activation of the ECS, especially under ischemic conditions, promotes CB1 expression and free radical production, which damages endothelial cells and accelerates the development of atherosclerosis. Inhibition of specific ECS receptors and enzymes has shown promise in reducing atherosclerosis complications, as evidenced by outcomes from major clinical trials (the Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant - the Intravascular Ultrasound Study [STRADIVARIUS]). These findings suggest that targeting the ECS may offer a novel therapeutic approach to managing atherosclerosis.