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• W2046870314 abstract "Starting from the well-documented effects of marijuana smoking on heart rate and blood pressure, the cardiovascular effects of Δ9-tetrahydrocannabinol (THC, the main psychotropic ingredient of Cannabis) and endocannabinoids [THC endogenous counterparts that activate cannabinoid receptor type 1 (CB1) and 2 (CB2)] have been thoroughly investigated. These studies were mostly aimed at establishing the molecular bases of the hypotensive actions of THC, endocannabinoids and related molecules, but also evaluated their therapeutic potential in cardiac injury protection, metabolic cardiovascular risk factors and atherosclerotic plaque vulnerability. The results of these investigations, reviewed here, also served to highlight some of the most peculiar aspects of endocannabinoid signaling, such as redundancy in endocannabinoid targets and the often dualistic role of CB1 and CB2 receptors during pathological conditions. Starting from the well-documented effects of marijuana smoking on heart rate and blood pressure, the cardiovascular effects of Δ9-tetrahydrocannabinol (THC, the main psychotropic ingredient of Cannabis) and endocannabinoids [THC endogenous counterparts that activate cannabinoid receptor type 1 (CB1) and 2 (CB2)] have been thoroughly investigated. These studies were mostly aimed at establishing the molecular bases of the hypotensive actions of THC, endocannabinoids and related molecules, but also evaluated their therapeutic potential in cardiac injury protection, metabolic cardiovascular risk factors and atherosclerotic plaque vulnerability. The results of these investigations, reviewed here, also served to highlight some of the most peculiar aspects of endocannabinoid signaling, such as redundancy in endocannabinoid targets and the often dualistic role of CB1 and CB2 receptors during pathological conditions. Since its discovery in the early 1990s, the ECS has increasingly emerged as a key signaling system involved in all physiological and pathological functions in mammals. This system comprises: (i) two G-protein-coupled receptors (GPCRs), known as cannabinoid receptors of type 1 (CB1) and 2 (CB2), named after the major psychotropic component of Cannabis sativa, Δ9-tetrahydrocannabinol (THC) (Figure 1), which binds and activates them; (ii) endogenous ligands for these two receptors, known as endocannabinoids, of which N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol (2-AG) (Figure 1) are the most studied examples; and (iii) proteins that regulate endocannabinoid tissue levels (anabolic and catabolic enzymes) and cellular distribution (endocannabinoid-binding proteins and transporters) or cannabinoid receptor activity (cannabinoid-receptor-interacting proteins) [1Di Marzo V. The endocannabinoid system: its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation.Pharmacol. Res. 2009; 60: 77-84Crossref PubMed Scopus (285) Google Scholar]. After nearly 20 years of active research, the ECS is now believed to play key roles in the control of nervous, metabolic, digestive, reproductive and immune functions, mainly (although not uniquely) via multiple and coordinated local and cell-specific modulatory effects over the release of neurotransmitters, neuropeptides, hormones and cytokines. Its general strategy of action is to help cells, tissues and organs to re-establish the physiological steady state after acute or chronic perturbations of their homeostasis. Like other pro-homeostatic systems, among which, however, it is perhaps the most ubiquitous and pleiotropic, the ECS may become dysregulated following prolonged perturbations of homeostasis, thus losing its specificity of action and contributing to the symptoms and/or progress of several pathological conditions [2Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce?.Nat. Rev. Drug Discov. 2008; 7: 438-455Crossref PubMed Scopus (662) Google Scholar]. Because of these features, the ECS has become a major focus for drug developers, who view pharmacological tools that regulate its activity as a unique opportunity to obtain new therapeutic tools targeting several disorders at the same time. This ambition, however, has been challenged by other peculiarities of the ECS, such as redundancy in the mechanisms underlying endocannabinoid biosynthesis and metabolism (often shared with endocannabinoid-like mediators) and the existence of endocannabinoid molecular targets other than CB1 and CB2 receptors [2Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce?.Nat. Rev. Drug Discov. 2008; 7: 438-455Crossref PubMed Scopus (662) Google Scholar]. Starting from the well-known effects of marijuana smoking and THC on blood pressure and heart rate [3Jones R.T. Cardiovascular system effects of marijuana.J. Clin. Pharmacol. 2002; 42: 58S-63SCrossref PubMed Scopus (216) Google Scholar], the ECS has been actively investigated in cardiovascular tissues. It is now clear that all the complications, apparent contradictions and hence challenges imposed by the mode of action of this signaling system can also be found in its emerging role in the regulation of cardiovascular homeostasis. Here we discuss the role of the ECS in the physiopathology of the cardiovascular system and highlight the typical features of endocannabinoid activity. Historically, the first cardiovascular studies on THC and endocannabinoids (namely anandamide) were carried out in anesthetized rodents. As later confirmed using CB1−/− and CB2−/− mice, these studies showed that both the initial bradycardic response and the prolonged hypotension that follow intravenous injection of cannabinoid receptor agonists are caused by activation of CB1 receptors [4Lake K.D. et al.Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors.J. Pharmacol. Exp. Ther. 1997; 281: 1030-1037PubMed Google Scholar, 5Wagner J.A. et al.Cardiovascular actions of cannabinoids and their generation during shock.J. Mol. Med. (Berl.). 1998; 76: 824-836Crossref PubMed Scopus (109) Google Scholar]. More recently, it was shown that a reduction in anandamide degradation is more effective at producing hypotension and cardiodepression than direct activation of CB1 with selective agonists [6Pacher P. et al.Hemodynamic profile, responsiveness to anandamide, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase.Am. J. Physiol. Heart Circ. Physiol. 2005; 289: H533-H541Crossref PubMed Scopus (80) Google Scholar]. Mice lacking fatty acid amide hydrolase (FAAH, an important hydrolytic enzyme for anandamide) – and therefore having higher basal anandamide levels – showed increased sensitivity to the in vivo cardiovascular effects of anandamide compared with wild-type mice [6Pacher P. et al.Hemodynamic profile, responsiveness to anandamide, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase.Am. J. Physiol. Heart Circ. Physiol. 2005; 289: H533-H541Crossref PubMed Scopus (80) Google Scholar]. However, anandamide also causes an initial steep hypotensive response that persists in CB1−/− and CB2−/− mice; it was later suggested that this is due to a Bezold–Jarisch reflex and results showed that it is mediated by activation of the transient receptor potential vanilloid type-1 (TRPV1) channel, a now a well-established alternative target of anandamide [7Malinowska B. et al.Anandamide and methanandamide induce both vanilloid VR1- and cannabinoid CB1 receptor-mediated changes in heart rate and blood pressure in anaesthetized rats.Naunyn Schmiedebergs Arch. Pharmacol. 2001; 364: 562-569Crossref PubMed Scopus (111) Google Scholar, 8Zygmunt P.M. et al.Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide.Nature. 1999; 400: 452-457Crossref PubMed Scopus (1829) Google Scholar]. To explore the molecular mechanism of its hypotensive effects, anandamide has been often investigated for its vasorelaxation effects in the rat mesenteric artery. This preparation was used originally to demonstrate anandamide activation of TRPV1 [8Zygmunt P.M. et al.Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide.Nature. 1999; 400: 452-457Crossref PubMed Scopus (1829) Google Scholar] and later to show that, surprisingly, THC can produce vasodilation independently of CB1 and CB2 receptor-mediated pathways by activating the transient receptor potential ankyrin type-1 (TRPA1) channel [9Jordt S.E. et al.Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1.Nature. 2004; 427: 260-265Crossref PubMed Scopus (1511) Google Scholar]. The vasodilatory effects of anandamide in the rat mesenteric artery are complex and involve many cellular and molecular mechanisms [10Hiley C.R. Ford W.R. Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling.Biol. Rev. Camb. Philos. Soc. 2004; 79: 187-205Crossref PubMed Scopus (55) Google Scholar]. These include the aforementioned stimulation of TRPV1 on perivascular neurons and subsequent release of vasodilatory peptides, and the participation of as yet unidentified endothelial receptors. These receptors are activated by abnormal cannabidiol (a synthetic cannabinoid inactive at CB1 and CB2 receptors), but not by THC, and are antagonized by the other most abundant cannabinoid in Cannabis, cannabidiol, as well as by a synthetic cannabinoid, O-1918. In addition, the vasodilatory effects of anandamide involve various types of Ca2+ and K+ channels, including Ca2+-activated K+ channels, possibly also as a consequence of abnormal cannabidiol receptor activation, as well as the formation of arachidonate metabolites originating from the enzymatic hydrolysis of anandamide (Figure 2). Because CB1 receptors do not transduce any vasodilatory actions of anandamide in the mesenteric artery, it is clear that these actions do not contribute much to the in vivo hypotensive effects of this endocannabinoid in anesthetized rodents [11Wagner J.A. et al.Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB1 receptors.Eur. J. Pharmacol. 2001; 423: 203-210Crossref PubMed Scopus (154) Google Scholar]. By contrast, the putative abnormal cannabidiol receptor participates in the delayed hypotensive effect of anandamide [12Járai Z. et al.Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors.Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 14136-14141Crossref PubMed Scopus (553) Google Scholar], whereas the TRPV1-mediated portion of the vasorelaxation effects of this endocannabinoid might be relevant under certain pathological conditions. In fact, high-salt-induced hypertension might be counteracted by anandamide via TRPV1 [13Wang Y. et al.Endocannabinoid regulates blood pressure via activation of the transient receptor potential vanilloid type 1 in Wistar rats fed a high-salt diet.J. Pharmacol. Exp. Ther. 2007; 321: 763-769Crossref PubMed Scopus (30) Google Scholar], whereas the hypotension accompanying cirrhosis appears to be partly due to anandamide acting at this channel, as well as CB1 [14Domenicali M. et al.Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats: role of cannabinoid and vanilloid receptors.Gut. 2005; 54: 522-527Crossref PubMed Scopus (94) Google Scholar]. However, because the TRPV1 blocker capsazepine, used in these studies, also has off- targets [15Ray A.M. et al.Capsazepine protects against neuronal injury caused by oxygen glucose deprivation by inhibiting Ih.J. Neurosci. 2003; 23: 10146-10153Crossref PubMed Google Scholar], caution should be used when evaluating the relevance of this channel in the vasorelaxation induced by anandamide, the hypotensive actions of which are completely absent in healthy mice when CB1 receptors are knocked out [16Ledent C. et al.Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice.Science. 1999; 283: 401-404Crossref PubMed Scopus (1085) Google Scholar]. Interestingly, it was also suggested that Ca2+-activated K+ channels partially mediate anandamide vasorelaxant effects on the mesenteric artery of rats with hepatic cirrhosis [17Yang Y.Y. et al.Role of Ca2+-dependent potassium channels in in vitro anandamide-mediated mesenteric vasorelaxation in rats with biliary cirrhosis.Liver Int. 2007; 27: 1045-1055Crossref PubMed Scopus (26) Google Scholar]. It was shown that the vasodilation by 2-AG depends on its hydrolysis to arachidonic acid and subsequent conversion to cyclooxygenase products [18Járai Z. et al.Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice.Hypertension. 2000; 35: 679-684Crossref PubMed Scopus (93) Google Scholar]. More recently, it was suggested that cytochrome p450 metabolites of 2-AG mediate the Ca2+-induced relaxation of rat mesenteric arteries [19Awumey E.M. et al.Cytochrome P-450 metabolites of 2-arachidonoylglycerol play a role in Ca2+-induced relaxation of rat mesenteric arteries.Am. J. Physiol. Heart Circ. Physiol. 2008; 294: H2363-H2370Crossref PubMed Scopus (37) Google Scholar]. The potent vasodilatory effect of another endocannabinoid, N-arachidonoyl dopamine, which is less abundant in tissues than anandamide and 2-AG and is also capable of activating TRPV1, is also quite complex. This compound relaxes the rat mesenteric artery via TRPV1 channels, abnormal-cannabidiol-sensitive receptors and CB1 receptors, with varying relative contributions by each of these mechanisms according to whether the superior mesenteric artery or small mesenteric vessels are used for experiments [20O'Sullivan S.E. et al.Characterisation of the vasorelaxant properties of the novel endocannabinoid N-arachidonoyl-dopamine (NADA).Br. J. Pharmacol. 2004; 141: 803-812Crossref PubMed Scopus (64) Google Scholar]. Despite these complex mechanisms, it has been shown that CB1 receptors activated by anandamide underlie hypotension in vivo in several experimental models of pathological conditions, including septic shock, hemorrhagic shock and myocardial infarction, and provide possible compensation against high blood pressure in spontaneously hypertensive rats [21Pacher P. et al.Cardiovascular pharmacology of cannabinoids.Handb. Exp. Pharmacol. 2005; 168: 599-625Crossref PubMed Scopus (5) Google Scholar]. Furthermore, use of AM3506 (a novel FAAH inhibitor) in rodents revealed that the antihypertensive effects of endogenously elevated anandamide levels occur via activation of CB1 receptors in the central nervous system and a reduction in sympathetic tone [22Godlewski G. et al.Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects.Chem. Biol. 2010; 17: 1256-1266Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. As mentioned above (Figure 1), several endogenous lipid mediators share a similar chemical structure and/or common metabolic pathways with anandamide (Figure 1), but do not activate CB1 or CB2 receptors (Figure 1). Many of these compounds were tested for their vasorelaxation effects in the rat mesenteric artery. Results showed that N-arachidonoyl-serine exerts this action via the abnormal-cannabidiol-sensitive endothelial receptor and activation of large conductance Ca2+-activated K+ channels [23Milman G. et al.N-Arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties.Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 2428-2433Crossref PubMed Scopus (141) Google Scholar], whereas N-arachidonoyl-glycine (a likely metabolite of anandamide [24Bradshaw H.B. et al.The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways.BMC Biochem. 2009; 10: 14Crossref PubMed Scopus (94) Google Scholar]) uses the latter mechanism as well as stimulation of nitric oxide (NO) [25Parmar N. Ho W.S. N-Arachidonoyl glycine, an endogenous lipid that acts as a vasorelaxant via nitric oxide and large conductance calcium-activated potassium channels.Br. J. Pharmacol. 2010; 160: 594-603Crossref PubMed Scopus (51) Google Scholar]. NO was also proposed as a downstream mediator for the TRPV1-mediated, albeit endothelial rather than sensory, mechanism of anandamide vasorelaxation in the same preparation [26Poblete I.M. et al.Anandamide elicits an acute release of nitric oxide through endothelial TRPV1 receptor activation in the rat arterial mesenteric bed.J. Physiol. 2005; 568: 539-551Crossref PubMed Scopus (94) Google Scholar]. Interestingly, it was recently found that N-arachidonoyl-glycine produces some other effects via the orphan GPCR GPR18 [27McHugh D. et al.N-Arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor.BMC Neurosci. 2010; 11: 44Crossref PubMed Scopus (226) Google Scholar], and it was suggested that this is the long-sought endothelial abnormal-cannabidiol-sensitive receptor. By contrast, the anandamide analogs N-oleoyl-ethanolamine (OEA) and N-palmitoyl-ethanolamine (PEA) enhance anandamide vasodilatory actions via entourage effects consisting of potentiation of anandamide activation of TRPV1 [28Ho W.S. et al.‘Entourage’ effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors.Br. J. Pharmacol. 2008; 155: 837-846Crossref PubMed Scopus (183) Google Scholar]. However, OEA itself also has effects that are exerted at the level of both sensory neurons and endothelium [29Wheal A.J. et al.Hydrogen peroxide as a mediator of vasorelaxation evoked by N-oleoylethanolamine and anandamide in rat small mesenteric arteries.Eur. J. Pharmacol. 2012; 674: 384-390Crossref PubMed Scopus (9) Google Scholar]. Preliminary results have also been reported on potential activity of GPR55 (another orphan receptor) in vasorelaxation [30Hiley C.R. Kaup S.S. GPR55 and the vascular receptors for cannabinoids.Br. J. Pharmacol. 2007; 152: 559-561Crossref PubMed Scopus (33) Google Scholar, 31Johns D.G. et al.The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects.Br. J. Pharmacol. 2007; 152: 825-831Crossref PubMed Scopus (192) Google Scholar]. GPR55 knockout mice did not show involvement of this receptor in the vasodilatory response to CB1/CB2 agonists or CB1/CB2-inactive cannabidiol [31Johns D.G. et al.The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects.Br. J. Pharmacol. 2007; 152: 825-831Crossref PubMed Scopus (192) Google Scholar]. In conclusion, several studies on the vasorelaxation effects of endocannabinoids in vitro suggest the existence of non-CB1, non-CB2 receptors for anandamide. These receptors (mainly TRP channels) might also mediate the vasodilatory effects of some non-psychotropic cannabinoids and endocannabinoid-like mediators. Together, these additional endogenous lipids and receptors might be part of an enlarged ECS, possibly defined as an endocannabinoid-like system (Figure 1). However, the role of these novel mediators and receptors in cardiovascular depressive responses must be confirmed by appropriate in vivo studies. Indeed, TRPV1 knockout mice display a normal cardiovascular profile in which anandamide-mediated effects in vivo are mainly mediated by CB1 receptors [32Pacher P. et al.Haemodynamic profile and responsiveness to anandamide of TRPV1 receptor knock-out mice.J. Physiol. 2004; 558: 647-657Crossref PubMed Scopus (99) Google Scholar]. Furthermore, knockout mice for endocannabinoid receptors or enzymes (such as FAAH, CB1, and CB2) are also characterized by normal cardiovascular function [6Pacher P. et al.Hemodynamic profile, responsiveness to anandamide, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase.Am. J. Physiol. Heart Circ. Physiol. 2005; 289: H533-H541Crossref PubMed Scopus (80) Google Scholar, 33Bátkai S. et al.Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury.FASEB J. 2007; 21: 1788-1800Crossref PubMed Scopus (217) Google Scholar, 34Mukhopadhyay P. et al.Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity.J. Am. Coll. Cardiol. 2007; 50: 528-536Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar]. Thus, these receptors and enzymes may not play a crucial role in the physiological regulation of the cardiovascular system unless the animal is challenged by certain pathological conditions. A reduction in cardiac damage after injury represents one of the most promising strategies for improving cardiac dysfunction. Both in vitro and in vivo models have strongly contributed to the identification of molecular mechanisms underlying cardiac injury and the consequent possible development of heart failure. In this context, it was recently shown that the ECS potentially modulates both acute and chronic cardiac disorders in response to ischemia–reperfusion and doxorubicin-induced injuries. Serious complications of these cardiomyopathies (such as cardiac arrhythmias) might also be regulated via activation of the ECS (Figure 3), with CB1 and CB2 receptors seemingly contributing to or opposing cardiomyocyte damage, respectively. Evidence from animal models of cardiac ischemia–reperfusion suggested that the ECS might protect the heart. In the isolated rat heart, PEA and 2-AG reduced myocardial infarct size [35Lépicier P. et al.Endocannabinoids protect the rat isolated heart against ischaemia.Br. J. Pharmacol. 2003; 139: 805-815Crossref PubMed Scopus (111) Google Scholar]. Interestingly, this beneficial effect was not observed with anandamide, confirming that different endocannabinoids might act through different cannabinoid receptors. Evidence of the potential involvement of CB2 and CB1 receptors was suggested using the selective antagonists SR144528 and SR141716A, respectively. Pretreatment with the CB2 antagonist abrogated the cardioprotective effect of both PEA and 2-AG, whereas a partial inhibitory effect on 2-AG-mediated activity was observed when the CB1 antagonist was used [35Lépicier P. et al.Endocannabinoids protect the rat isolated heart against ischaemia.Br. J. Pharmacol. 2003; 139: 805-815Crossref PubMed Scopus (111) Google Scholar]. However, PEA cannot directly activate CB1 or CB2 receptors, but previous data suggested that SR144528 can act nonspecifically and antagonize another proposed target for this compound, peroxisome proliferator-activated receptor (PPAR)-α [36Lo Verme J. et al.The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide.Mol. Pharmacol. 2005; 67: 15-19Crossref PubMed Scopus (689) Google Scholar]. Alternatively, PEA can enhance the activity of endocannabinoids not only at TRPV1 channels, as mentioned above [28Ho W.S. et al.‘Entourage’ effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors.Br. J. Pharmacol. 2008; 155: 837-846Crossref PubMed Scopus (183) Google Scholar], but also at cannabinoid receptors [37Di Marzo V. et al.Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells.Biochem. J. 2001; 358: 249-255Crossref PubMed Scopus (173) Google Scholar]. The role of the ECS in reducing ischemic injury was also investigated using CB1 and CB2 antagonists in an isolated rat heart model of preconditioning. Perfusion with the CB2 antagonist SR144528, but not the CB1 antagonist SR141716A, abrogated the beneficial effects of LPS treatment [38Lagneux C. Lamontagne D. Involvement of cannabinoids in the cardioprotection induced by lipopolysaccharide.Br. J. Pharmacol. 2001; 132: 793-796Crossref PubMed Scopus (89) Google Scholar]. Similarly, ex vivo perfusion with the CB2 antagonist SR144528 reduced the protective effects of in vivo heat stress preconditioning on infarct size [39Joyeux M. et al.Endocannabinoids are implicated in the infarct size-reducing effect conferred by heat stress preconditioning in isolated rat hearts.Cardiovasc. Res. 2002; 55: 619-625Crossref PubMed Scopus (83) Google Scholar], suggesting a protective role for CB2 activation in ischemia–reperfusion injury. The beneficial effect of CB2 activation on myocardial infarction in mice was recently confirmed in models of ischemia and reperfusion in vivo [40Montecucco F. et al.CB2 cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion.J. Mol. Cell Cardiol. 2009; 46: 612-620Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 41Defer N. et al.The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy.FASEB J. 2009; 23: 2120-2130Crossref PubMed Scopus (99) Google Scholar]. Interestingly, these studies independently showed that selective activation of the CB2 receptor a few minutes before reperfusion markedly improves myocardial infarction. This suggests a potential therapeutic value of a one-shot secondary prevention approach with a CB2 agonist, which could easily be performed during interventional procedures in the catheterization laboratory [40Montecucco F. et al.CB2 cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion.J. Mol. Cell Cardiol. 2009; 46: 612-620Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. To investigate the molecular mechanisms underlying CB2-mediated therapeutic effects, the pathophysiology of both cardiomyocytes and inflammatory cells was explored. Ex vivo, the endocannabinoid-like molecule PEA enhanced protective phosphorylation of p38 mitogen-activated protein kinase (MAPK) and ERK1/2 within infarcted myocardium [35Lépicier P. et al.Endocannabinoids protect the rat isolated heart against ischaemia.Br. J. Pharmacol. 2003; 139: 805-815Crossref PubMed Scopus (111) Google Scholar]. This beneficial effect was exclusively abrogated by pretreatment with the selective CB2 antagonist SR144528, suggesting that activation of this receptor (or of PPAR-α, see above) is a pivotal cardioprotective trigger. In vivo, a beneficial increase in activation of ERK1/2 (and of the STAT3-mediated pathway) was confirmed by treating mice with the synthetic selective CB2 agonist JWH-133 [40Montecucco F. et al.CB2 cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion.J. Mol. Cell Cardiol. 2009; 46: 612-620Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. Because early activation of these intracellular pathways is crucial for the salvage of ischemic cardiomyocytes, selective activation of CB2 should be considered for direct targeting of cardiac cells. CB2 activation also reduced neutrophil migration within infarcted ventricles in vivo and in vitro [40Montecucco F. et al.CB2 cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion.J. Mol. Cell Cardiol. 2009; 46: 612-620Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. Treatment with the selective CB2 agonist JWH-133 attenuated neutrophil recruitment towards proinflammatory cytokines [such as tumor necrosis factor (TNF)-α] released after acute myocardial infarction. In addition, cannabidiol protects the heart from oxidant-mediated deleterious effects in vivo [42Rajesh M. et al.Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption.Am. J. Physiol. Heart Circ. Physiol. 2007; 293: H610-H619Crossref PubMed Scopus (145) Google Scholar, 43Rajesh M. et al.Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.J. Am. Coll. Cardiol. 2010; 56: 2115-2125Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 44Durst R. et al.Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury.Am. J. Physiol. Heart Circ. Physiol. 2007; 293: H3602-H3607Crossref PubMed Scopus (78) Google Scholar]. Cannabidiol has antioxidant properties and only weak affinity for CB1 and CB2 receptors, but it may act via mechanisms, such as TRPV1 activation and FAAH inhibition [45Bisogno T. et al.Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide.Br. J. Pharmacol. 2001; 134: 845-852Crossref PubMed Scopus (783) Google Scholar], that are involved in cardiovascular function (see above). In particular, cannabidiol was selectively effective against myocardial complications of diabetic cardiomyopathy, ameliorating cardiac function via a reduction in oxidant release (Figure 2) [43Rajesh M. et al.Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.J. Am. Coll. Cardiol. 2010; 56: 2115-2125Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar]. Because oxidants might contribute to cardiomyocyte ischemia–reperfusion injury [46Montecucco F. et al.Single administration of the CXC chemokine-binding protein Evasin-3 during ischemia prevents myocardial reperfusion injury in mice.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 1371-1377Crossref PubMed Scopus (64) Google Scholar], chronic treatment with cannabidiol in the first days after acute myocardial infarction was also performed in rats [44Durst R. et al.Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury.Am. J. Physiol. Heart Circ. Physiol. 2007; 293:" @default.
• W2046870314 created "2016-06-24" @default.
• W2046870314 creator A5007484138 @default.
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• W2046870314 date "2012-06-01" @default.
• W2046870314 modified "2023-10-09" @default.
• W2046870314 title "At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction" @default.
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