Modulation of the endocannabinoid system in cardiovascular disease: therapeutic potential and limitations.

Endocannabinoids, endogenous lipid mediators generated by virtually all cell types both in the brain and peripheral tissues, elicit a broad range of biological effects similar to those of marijuana. The endocannabinoid system (ECS) comprises the endocannabinoids, the enzymes involved in their biosynthesis and degradation, putative membrane transporter(s) involved in their cellular uptake and (possibly) release, and the G protein-coupled receptors that mediate their effects, including CB1 and CB2 as well as additional, as yet unidentified, receptors.1–4 GPR55 has recently been proposed to be a cannabinoid receptor,5 although its in vivo biological functions have not yet been identified. Arachidonoyl ethanolamide (anandamide [AEA]) and 2-arachidonoylglycerol are the 2 best characterized endocannabinoids. AEA can be a full or partial agonist at CB1 receptors, depending on the system, and has low efficacy at CB2 receptors, whereas 2-arachidonoylglycerol is a full agonist at both CB1 and CB2 receptors. AEA also binds to vanilloid VR1 receptors, although with an affinity an order of magnitude lower than its affinity for CB1 receptors.3 Both AEA and 2-arachidonoylglycerol are generated in the cell membrane from membrane phospholipid precursors, and the synthesis of both ligands involves multiple, parallel biosynthetic pathways.4,6,7 In contrast, their enzymatic degradation occurs through unique pathways, AEA being degraded primarily by fatty acid amidohydrolase (FAAH),8 whereas 2-arachidonoylglycerol is degraded mainly by monoglyceride lipase, although additional enzymes may make a minor contribution to the in vivo degradation of both ligands.9 In the absence of a cellular storage mechanism for endocannabinoids, their tissue levels are determined by the balance between the rate of their “on-demand” synthesis and their enzymatic degradation. The CB1 receptor is predominantly expressed in the central nervous system,3 but is also present at much lower, yet functionally relevant, levels in various peripheral tissues, including the myocardium,10–12 postganglionic autonomic nerve terminals,3 and vascular endothelial and smooth muscle cells13,14 as well as the adipose tissue,15,16 liver,16–19 and skeletal muscle.20 Expression of CB2 receptors was thought to be limited to hematopoietic and immune cells, but they have recently been identified in the brain,21 liver,19 myocardium,12 and human coronary endothelial and smooth muscle cells.13,14 In addition to Gi/o-dependent pathways, CB1 and CB2 receptors may also signal through other G proteins as well as through G protein-independent pathways.22 Activation of the ECS has been implicated in CB1mediated hypotension associated with hemorrhagic, septic, cardiogenic shock, advanced liver cirrhosis (reviewed in 3), and doxorubicin-induced heart failure.12 Increased ECS activity also contributes to the generation of cardiovascular risk factors in obesity/metabolic syndrome and diabetes such as plasma lipid alterations, abdominal obesity, hepatic steatosis, and insulin and leptin resistance.23–28 However, the ECS may also be activated as a compensatory mechanism in various forms of hypertension where it counteracts not only the increase in arterial pressure, but also the inappropriately increased cardiac contractility through activation of CB1 receptors.11,29 In addition, the activation of CB2 receptors in endothelial and inflammatory cells by endogenous or exogenous ligands was found to limit the endothelial inflammatory response, chemotaxis, and adhesion of inflammatory cells to the activated endothelium with the consequent release of various proinflammatory mediators, which are key processes in the initiation and progression of atherosclerosis and reperfusion injury13,30–33 as well as smooth muscle proliferation.14 Therefore, depending on the underlying pathology, selective activation of CB1 or CB2 receptors or inhibition of CB1 receptors may offer therapeutic benefits (Figures 1 and 2).