The emerging role of the endocannabinoid system in cardiovascular disease

Abstract

Endocannabinoids are endogenous bioactive lipid mediators present both in the brain and various peripheral tissues, which exert their biological effects via interaction with specific G-protein-coupled cannabinoid receptors, the CB(1) and CB(2). Pathological overactivation of the endocannabinoid system (ECS) in various forms of shock and heart failure may contribute to the underlying pathology and cardiodepressive state by the activation of the cardiovascular CB(1) receptors. Furthermore, tonic activation of CB(1) receptors by endocannabinoids has also been implicated in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes, such as plasma lipid alterations, abdominal obesity, hepatic steatosis, inflammation, and insulin and leptin resistance. In contrast, activation of CB(2) receptors in immune cells exerts various immunomodulatory effects, and the CB(2) receptors in endothelial and inflammatory cells appear to limit the endothelial inflammatory response, chemotaxis, and inflammatory cell adhesion and activation in atherosclerosis and reperfusion injury. Here, we will overview the cardiovascular actions of endocannabinoids and the growing body of evidence implicating the dysregulation of the ECS in a variety of cardiovascular diseases. We will also discuss the therapeutic potential of the modulation of the ECS by selective agonists/antagonists in various cardiovascular disorders associated with inflammation and tissue injury, ranging from myocardial infarction and heart failure to atherosclerosis and cardiometabolic disorders.

Fig. 1

Therapeutic targets of CB₂ receptor stimulation in ischemia/reperfusion injury and atherosclerosis. CB₂ agonists decrease endothelial cell activation and inflammatory response, chemotaxis triggered by inflammatory stimuli/chemokines, and adhesion of inflammatory cells (lymphocytes, neutrophils, and/or monocytes) to activated endothelium, transendothelial migration of inflammatory cells, attachment to parenchymal cells, and activation. In addition, CB₂ activation may also mediate direct protective effects in cardiomyocytes and decrease smooth muscle cell proliferation/migration. Reproduced with permission from American Heart Association from [35]

Fig. 2

Selected beneficial effects of CB₁ receptor blockade with rimonabant observed in preclinical/clinical studies with potential relevance to atherosclerosis and cardiovascular diseases/risk. Modified with the permission of the American Heart Association from [94]