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 CB1 and CB2. 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 CB1 receptors. Furthermore, tonic activation of CB1 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 CB2 receptors in immune cells exerts various immunomodulatory effects, and the CB2 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.

Association of polymorphisms in the endocannabinoid system genes with myocardial infarction and plasma cholesterol levels

“…Blockade of AEA degradation by FAAH inhibition increases myocardial levels of AEA and results in decrease of blood pressure and heart rate especially in hypertensive states due to reduction of contractility and vascular resistance 11 . While chronic elevation of plasma AEA seems to have a negative effect on vasculature, acute elevations may be athero-protective 12,13 . Common C to A substitution in the position 385 (rs324420) in the FAAH gene (chromosome 1p35-p34) results in proline to threonine substitution (P129T) with reduced expression and stability of mutant enzyme form 14 .…”

“…Endocannabinoids (ECS) are endogenous lipid mediators with a wide range of biological effects similar to those of tetrahydrocannabinol, the principal active component of Cannabis sativa. ECS are produced by virtually all cell types, however the most important sources of ECS are vascular smooth muscle cells, endothelial cells, nerve cells within the blood vessel walls and circulating blood cells 2,3 . Two most widely studied ECS are anandamide (AEA) and 2-arachidonoylglycerol (2-AG) (ref.…”

Cannabinoids, the Heart of the Matter

“…In addition, ∆‐9‐THC‐stimulated human T‐cells show less proliferation and inhibition of interferon‐gamma production, as well as downregulation of T‐helper 1 cells78 that are present in atherosclerotic lesions and which contribute to the inflammatory state of the lesions. The endocannabinoid system (ECS) and cannabinoid receptors (both CB1 and CB2) are highly active in cells found in atherosclerotic plaques such as macrophages and vascular smooth muscle cells 2, 79. Macrophages are activated by oxidized LDL through increased (anandamide) and 2‐arachidonoylglycerol (2‐AG) concentration, as well as upregulation of CB1 and CB2, thus initiating cholesterol accumulation in immune cells, affecting endothelial cells, and vascular smooth muscle cells 2, 79, 80…”

“…This review highlights the potential of cannabinoids and their receptors as targets for intervention. The endocannabinoid system (ECS) is upregulated in cardiovascular disease states, and cannabinoids in general influence disease progression 2. Moreover, there are paradoxical indications as to whether therapies directed at the ECS, or exogenous drugs derived from marijuana, could have therapeutic impact in CVD.…”

Endocannabinoid system and cannabinoids in neurogenesis – new opportunities for neurological treatment? Reports from experimental studies.

“…AEA and 2-arachidonoylglycerol are known to regulate human cardiovascular functions and homeostasis [8]. AEA has been shown to control the cell choice between growth and death, and 2-AG was shown to be a direct substrate of the cyclooxygenase COX and lipoxygenase LOX pathway [9].…”