At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction  Fabrizio Montecucco, Vincenzo Di Marzo  Trends in Pharmacological Sciences  Volume 33, Issue 6, Pages 331-340 (June 2012) DOI: 10.1016/j.tips.2012.03.002 Copyright © 2012 Elsevier Ltd Terms and Conditions

Figure 1 Cannabinoids, endocannabinoids, endocannabinoid-like molecules and proteins of the endocannabinoid system in vascular tissues. Chemical structures of (a) plant cannabinoids, (b) endocannabinoids and (c) endocannabinoid-like molecules that have been most thoroughly investigated for their cardiovascular actions. (a) Plant cannabinoids Δ9-tetrahydrocannabinol (THC, which activates cannabinoid receptors CB1 and CB2) and cannabidiol (CBD), and the synthetic analog abnormal cannabidiol (ABN-CBD) (which, like CBD, has very low affinity for CB1 and CB2 receptors). (b) The three endocannabinoids 2-arachidonoyl glycerol (2-AG), anandamide (AEA) and N-arachidonoyl dopamine (NADA). (c) Some endocannabinoid-like molecules with low affinity for CB1 and CB2 receptors: N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA), N-arachidonoyl serine and N-arachidonoyl glycine. (d) Current knowledge of the distribution of molecularly characterized targets for 2-AG (CB1, CB2), AEA (CB1, CB2, TRPV1) and NADA (CB1, CB2, TRPV1), and of biosynthesizing (N-arachidonoyl-phosphatidylethanolamine-selective phospholipase D, NAPE-PLD) and hydrolytic (fatty acid amide hydrolase-1, FAAH) enzymes for AEA in cells of vascular tissues, as demonstrated so far by immunohistochemistry or quantitative PCR. EC, endothelial cells; SMC, smooth muscle cells; NT, sensory or sympathetic neuron terminals. Trends in Pharmacological Sciences 2012 33, 331-340DOI: (10.1016/j.tips.2012.03.002) Copyright © 2012 Elsevier Ltd Terms and Conditions

Figure 2 Summary of the mechanisms of the relaxing effects of the endocannabinoid and endocannabinoid-like systems in mesenteric and other arteries. As detailed in the text, anandamide (AEA) and N-arachidonoyl dopamine (NADA) induce relaxation of mesenteric arteries via several differently located molecular targets, in particular (i) transient receptor potential vanilloid type-1 (TRPV1) channels in sensory neurons, with subsequent release of calcitonin gene-related peptide (CGRP) and smooth muscle hyperpolarization, and (ii) abnormal cannabidiol and pertussis toxin-sensitive receptors (denoted as X but possibly identical to GPR18) in endothelial cells. This results either in the activation of calcium-dependent potassium channels (BKCa) and hyperpolarization of smooth muscle cells, or, following activation of the cGMP cascade, in the release of an as yet unidentified endothelial-dependent hyperpolarizing factor (EDHF) acting on BKCa in smooth muscle cells. Other mechanisms have also been proposed for the hyperpolarization of smooth muscle cells, such as activation of gap junctions and TRPV1-mediated production of nitric oxide (NO) from endothelial cells. In other artery types, AEA might also act at CB1 receptors in smooth muscle or endothelial cells. In vivo, AEA, like other CB1 agonists (CBAs), is also likely to induce vasodilation via inhibition of catecholamine release from sympathetic nerves. Δ9-Tetrahydrocannabinol (THC), unlike AEA or synthetic CB1 agonists, can relax the mesenteric artery via transient receptor potential ankyrin type-1 (TRPA1) channels in sensory neurons. Finally, various endocannabinoid-like mediators, such as N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA), oleamide (OA), N-arachidonoyl serine (NASer) and N-arachidonoyl glycine (NAGly), induce vasorelaxation of mesenteric arteries through some of these same mechanisms. Trends in Pharmacological Sciences 2012 33, 331-340DOI: (10.1016/j.tips.2012.03.002) Copyright © 2012 Elsevier Ltd Terms and Conditions

Figure 3 Pathophysiological role of the endocannabinoid system in cardioprotection. Schematic heart transverse sections at the mid-ventricular level (papillary muscles) are shown for different conditions (a–e) in which the endocannabinoid system potentially plays an active role. (a) Myocardial ischemia and reperfusion (I/R) injury is represented by a heart section showing a necrotic zone with infiltrating inflammatory cells (white zone on the left ventricle with spots of inflammatory cells). It has been shown that activation of the CB2 receptor reduces infarct size and arrhythmia complications in rodent models of I/R. (b) An apparently healthy heart is represented by a section of normal color without any remodeling or injured area. In human subjects with apparently healthy hearts, the potential role of endocannabinoids in cardiac arrhythmias is still unknown and requires further investigation. (c) Doxorubicin (Dox)-induced cardiotoxicity is shown as a section of a dilated heart (adverse cardiac remodeling) in light brown (caused by collagen deposition between cardiomyocytes). (d) Cirrhotic cardiomyopathy is represented as a cardiac section of normal color (cardiomyocytes are still present) but characterized by adverse cardiac remodeling (left ventricle hypertrophy and diastolic dysfunction). (e) Diabetic cardiomyopathy is represented by a heart section of increased left ventricular mass and dilated ventricles. The color is light brown and in some parts it tends to white because of the presence of cardiac fibrosis. In Dox-induced cardiotoxicity and cardiomyopathies associated with hepatic cirrhosis and diabetes (c–e), CB1 antagonism represents a promising strategy for reducing cardiac injury. Trends in Pharmacological Sciences 2012 33, 331-340DOI: (10.1016/j.tips.2012.03.002) Copyright © 2012 Elsevier Ltd Terms and Conditions

Figure 4 Role of the endocannabinoid system in atherogenesis. CB1 upregulation and CB2 downregulation have been associated with vulnerability in different regions (upstream vs downstream the blood flow) of human plaques and also depend on shear stress forces (low shear stress, LSS; high shear stress, HSS; oscillatory shear stress, OSS). Treatments producing selective CB1 blockade or CB2 activation might improve atherogenesis by reducing the inflammation of atherosclerosis plaques and decrease the risk of cardiovascular events by enhancing plaque stability. Trends in Pharmacological Sciences 2012 33, 331-340DOI: (10.1016/j.tips.2012.03.002) Copyright © 2012 Elsevier Ltd Terms and Conditions