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Abstract

Our current understanding of the pathophysiology of atherosclerosis suggests a prominent role for immune responses from its initiation through its complications. Given the increasing prevalence of cardiovascular risk factors worldwide, there is an urgent need to better understand the underlying mechanisms to improve current treatment protocols. A growing body of evidence suggests that endocannabinoid signalling plays a critical role in the pathogenesis of atherogenesis and its clinical manifestations. Blocking CB(1) receptors has been shown to mediate not only weight reduction, but also several cardiometabolic effects in rodents and humans, indicating a potential relevance for the process of atherosclerosis. Activation of CB(2) receptors with Delta(9)-tetrahydrocannabinol (THC) has been shown to inhibit atherosclerotic plaque progression in mice, mainly by inhibiting macrophage recruitment. Endocannabinoids released from endothelial cells, macrophages or platelets, reduce hypertension in rodents, a major risk factor for atherosclerosis. In addition, anandamide inhibits inflammatory gene expression in endothelial cells, and consequently monocyte adhesion. Conversely, endocannabinoids might also mediate pro-atherosclerotic effects by inducing platelet activation. In conclusion, the precise role of the endocannabinoid system during atherosclerosis is not yet understood. Whether increased endocannabinoid signalling is associated with disease progression and increased risk of acute thrombotic events remains to be determined.

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... Increasing evidence suggests that endocannabinoid signalling plays a critical role in atherogenesis. CB2R activation by D9-THC inhibits atherosclerotic plaque progression in mice by inhibiting macrophage recruitment, and AEA inhibits inflammatory gene expression in endothelial cells and consequently monocyte adhesion (Mach and Steffens 2008). CB2R may influence atherosclerosis by modulating lesional macrophage apoptosis (Freeman-Anderson et al. 2008). ...
... CB2R may influence atherosclerosis by modulating lesional macrophage apoptosis (Freeman-Anderson et al. 2008). Endocannabinoids may also mediate pro-atherosclerotic effects by inducing platelet activation (Mach and Steffens 2008). Recently, it was demonstrated that 2-AG, PEA and OAE levels were altered in the aorta and visceral adipose tissue in a mouse model of atherosclerosis (Montecucco et al. 2009). ...
Article
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Studies of the last 40 years have brought to light an important physiological network, the endocannabinoid system. Endogenous and exogenous cannabinoids mediate their effects through activation of specific cannabinoid receptors. This modulatory homoeostatic system operates in the regulation of brain function and also in the periphery. The cannabinoid system has been shown to be involved in regulating the immune system. Studies examining the effect of cannabinoid-based drugs on immunity have shown that many cellular and cytokine mechanisms are modulated by these agents, thus raising the hypothesis that these compounds may be of value in the management of chronic inflammatory diseases. The special properties of endocannabinoids as neurotransmitters, their pleiotropic effects and the impact on immune function show that the endocannabinoid system represents a revolving plate of neural and immune interactions. In this paper, we outline current information on immune effects of cannabinoids in health and disease.
... Recent evidence has documented that CB 1 R and CB 2 R expression increases in murine foam cells, and so do the levels of AEA and 2-AG [13]. Moreover, CB 1 R has been clearly associated with cardiometabolic risk factors, including obesity and increased serum lipid production [14,15]. In particular, pre-clinical murine models of atherosclerosis indicate that pharmacological inhibition of CB 1 R reduces oxLDL accumulation in macrophages, limits the vascular inflammation and associated disease progression, and also decreases smooth muscle cells proliferation [14,15]. ...
... Moreover, CB 1 R has been clearly associated with cardiometabolic risk factors, including obesity and increased serum lipid production [14,15]. In particular, pre-clinical murine models of atherosclerosis indicate that pharmacological inhibition of CB 1 R reduces oxLDL accumulation in macrophages, limits the vascular inflammation and associated disease progression, and also decreases smooth muscle cells proliferation [14,15]. Conversely, CB 1 R activation induces reactive oxygen species and cell death in human coronary artery endothelial cells [16], supporting beneficial effects of CB 1 R antagonists in humans with obesity and/or diabetes and metabolic syndrome [17,18]. ...
Article
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Objective Cannabinoid receptors are activated in murine macrophages upon exposure to oxidized low-density lipoproteins (oxLDL), and type-1 cannabinoid receptor (CB1R) is considered as a risk factor in atherosclerosis, because it promotes cholesterol accumulation and release of inflammatory mediators. Conversely, accumulated evidence suggests a protective role for type-2 cannabinoid receptor (CB2R). Here, we sought to ascertain whether different elements of the endocannabinoid system (ECS) were activated in human lipid-laden macrophages, and whether CB2R played any role in atherogenesis and inflammation of these cells. Methods and results Human macrophages were exposed to oxLDL in order to obtain lipid-laden foam cells. Liquid chromatography/mass spectrometry (LC/MS) was used to measure the production of the endocannabinoids in both macrophages and foam cells, and radiometric assays were performed to measure cannabinoid receptor binding and activity of endocannabinoid metabolizing enzymes. OxLDL accumulation was investigated by confocal imaging, and cytokine production and release were measured by means of flow cytometry and ELISA. The results showed that human macrophages possess a fully functional ECS, which was modulated by oxLDL. Selective CB2R activation reduced cellular oxLDL accumulation, which was associated with decreased expression of CD36 scavenger receptor, and decreased production of TNFα, IL-12 and IL-10. These anti-atherogenic and anti-inflammatory effects were reverted by the selective CB2R antagonist SR144528. Conclusions A fully active ECS is present in human macrophages and macrophage-derived foam cells. Selective activation of CB2R reduces CD36-dependent oxLDL accumulation and modulates production of inflammatory cytokines, thus representing a potential therapeutic strategy to combat atherosclerosis.
... The ES has been also involved in the physiopathology of vascular diseases through multiple pathways [28,29]. The effect of the ES on atherosclerosis may be ambivalent. ...
... The effect of the ES on atherosclerosis may be ambivalent. Activation of CB1Rs favor atherogenic inflammation, stimulating immune cell migration and inducing platelet activation, promotes excessive foot intake and adipose tissue formation, and contributes to a negative cardiovascular risk profile (including plasma lipid alteration and insulin and leptin resistance) in patients with obesity, diabetes, or metabolic syndrome [29,30]. Conversely, CB1R activation may dampen hypertension while the CB2R pathway has an anti-atherogenic activity mediated by its anti-oxidant properties, and by the modulation of inflammation (monocyte and macrophage recruitment) as well as of activation of vessel wall cell (smooth muscle cells and endothelium) [31]. ...
Article
Growing evidence suggests that the endocannabinoid system is involved in the pathogenesis of Alzheimer's disease (AD) and atherosclerosis. The purpose of this study was to investigate the activation of the endocannabinoid system in AD in vivo and the possible intermediate role of atherosclerosis. We enrolled 41 patients with probable AD, and 30 age- and gender-matched controls. All subjects underwent: ultrasound examination of cerebral and neck vessels (including intima-media thickness and plaque stenosis evaluation); blood sampling to measure levels of endocannabinoid [anandamide (AEA), 2-arachidonoylglycerol (2-AG)] and endogenous AEA analogues [N-palmitoyl-ethanolamide (PEA); N-oleoyl-ethanolamide]; neuropsychological evaluation and brain MRI (atrophy, white matter hyperintensity volume). 2-AG levels were higher in AD patients compared to controls (Mann-Whitney test p = 0.021). In the AD group, 2-AG correlated to white matter hyperintensity volume (r = 0.415, p = 0.015) and was higher in patients with chronic heart ischemic disease (p = 0.023). In AD patients, 2-AG was also positively related to memory (r = 0.334, p = 0.05) and attention (r = 0.423, p = 0.018) performances. Constructional praxia test scores were lower in patients with higher levels of PEA (r = -0.389, p = 0.019). AD patients present high plasma 2-AG levels, also in relation to heart ischemic disease and cerebral leukoaraiosis. This may be a protective mechanism hindering neurodegeneration, but it may also play an ambivalent role on cerebrovascular circulation. The increase in 2-AG and PEA levels observed with ongoing pathological processes may differently modulate cognitive performances.
... Other components of this system include receptors, namely cannabinoid receptor type-1 (CB1) and cannabinoid receptor type-2 (CB2), and enzymes for biosynthesis and degradation of ligands [18]. Increased AEA and 2-AG levels may play a role in atherosclerosis development via platelet activation and prothrombotic effects [19]. Observational studies have revealed a correlation between elevated levels of AEA and 2-AG in hypercholesterolemic mice and proatherosclerotic effects [20]. ...
... CB1/CB2 receptors play different roles in atherosclerosis development. CB1 activation results in a proinflammatory response through production of reactive oxygen species in macrophages derived from human atheroma, whereas activation of CB2 receptors modulates immune challenges on immune cells [19] and decreases tumor necrosis factor-alpha (TNF-α) production which may suppress the atherosclerosis process [23,24]. Therefore, the beneficial effects of omega-3-rich oils can be partly attributed to CB2-mediated effects in ECS. ...
Article
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Background: The endocannabinoid system (ECS) overactivation, associated with increased inflammatory process, may act as a risk factor for coronary artery disease (CAD). Dietary fat may influence the ECS tone. The aim of the present study was to investigate the effect of flaxseed oil on the erythrocyte membrane fatty acid profile and ECS activity by the measurement of serum N-arachydonoil ethanolamine (AEA) and cannabinoid receptor type-1 (CB1), cannabinoid receptor type-2 (CB2), and fatty acid amide hydrolase (FAAH) mRNA expression. Methods: This clinical trial was performed on 44 patients with CAD. The intervention group received 1.5% fat milk supplemented with flaxseed oil (containing 2.5 g α-linolenic acid or ALA), while the placebo group received 1.5% fat milk for 10 weeks. The fatty acid profile of erythrocyte membrane phospholipids was measured by gas chromatography. The AEA level was determined using an ELISA kit, and real-time PCR was performed to measure CB1, CB2, and FAAH mRNA expression pre- and post-intervention. Results: Flaxseed oil supplementation resulted in a significant increase in the ALA content and a significant reduction in linoleic acid (LA) content of membrane phospholipids, compared to the placebo group (MD = - 0.35 and 2.89, respectively; P < 0.05). The within group analysis showed that flaxseed oil supplementation caused a significant reduction in both LA and arachidonic acid (MD = - 4.84 and - 4.03, respectively; P < 0.05) and an elevation in the ALA (MD = 0.37, P < 0.001) content of membrane phospholipids compared with the baseline. In the intervention group, a marked reduction was observed in the serum AEA level after 10 weeks of intervention, compared with the placebo group (MD = 0.64, P = 0.016). Changes in CB2 mRNA expression in the flaxseed oil group were significant (fold change = 1.30, P = 0.003), compared with the placebo group. Conclusion: Flaxseed oil supplementation could attenuate the ECS tone by decreasing the AEA level and increasing CB2 mRNA expression. Therefore, flaxseed oil may be considered a promising agent with cardioprotective properties.
... Another possible mechanism in which marijuana usecanleadtoCADisviatheactivationofproinflammatory molecules and their pathway in the coronary vasculature. Cannabinoids have shown to potentiate the production of arachidonic acid by causing inflammation that leads to the production of its precursor, 2-Arachidonoylglycerol (2-AG) [17,18]. Also, THC was found to increase cyclooxygenase 1 and 2 (COX-1, COX-2) levels and causes thromboxane A2 and subsequent prostaglandin production in animal models [19]. ...
... The effect of THC on platelets are not limited to its interaction with arachidonic acid, as it also induces platelet aggregation by potentiating Glycoprotein IIa/IIIb and P-selectin expression via the activation of CB 1 and CB 2 receptors [17,20]. The aforementioned arachidonic acid precursor, 2-AG also potentiates platelet aggregation by inducing phosphorylation of platelet actin molecules through the action of myosin light chain kinase, which subsequently results in platelet conformational change and aggregation. ...
Article
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Background Marijuana use has been increasingly legalized in the United States resulting in substantial rise in the number of users especially in the younger populations. While our group and others had described various metabolic effects of this drug, little is known about its association with acute myocardial infarction (AMI). Objective This follow up study presents contemporaneous cohort of non-THC user patients at a single, urban center hospital diagnosed with ST-elevation AMI; highlighting and comparing demographic, clinical, laboratory and angiographic characteristics based on exposure to THC at time of presentation. Methods Retrospective chart review of patients with ST-elevation AMI presenting to our inner city hospital Coronary Care Unit over a period of 4 years (December 2013–April 2017). Results Of the 10 case subjects studied whom presented with chest pain, EKG evidence of ST-elevation MI (STEMI) with cannabis use, mean age at presentation was 40 years old, which was 10 years younger than our control group with no marijuana use (n = 11, p = 0.107). Of the patients who had marijuana exposure upon admission, 3 (30%) had no known cardiovascular disease (CVD) risk factors (RF) on admission, 1 patient had 3 RF, 4 patients had 2 RF and 2 had 1 CVD risk factor, which included age, diabetes mellitus type 2 (DM2), hypertension, dyslipidemia, smoking status, and family history at time of triage. Patients who were negative for marijuana use had higher number of CVD risk factors present upon admission. ASCVD risk scores were 10% vs. 16% (p = 0.312). In angiographic findings, 100% of the marijuana users had 1 vessel disease compared with 55% in the non-users (p = 0.0351). Severity of stenosis for both groups was averaged at 93% for non-users vs 95% in THC users (p = 0.62414). Collateral vessels were visible during coronary arteriogram in 91% of non-THC users and in only 20% of THC users (p = 0.0019). Furthermore, non-users had 35% higher rate of Rentrop grade 1 collaterals (55% vs. 20%, p = 0.4872). Similar difference was shown in grade 2 collaterals between the two groups with non-users having 36% higher rate (36% vs. 0%, p = 0.0902). Amongst the patients who had collateral circulation present at the time of angiography (Rentrop grade >0), good collaterals (Rentrop grade 2 or 3) were present in 40% of non-THC users, while there was 0% presence of grade 2+ collaterals in THC users (p = 0.5152). Conclusion In our study, marijuana use is associated with ST-elevation MI in largely minority population, occurring at a relatively younger age with half of the cases CVD risk free. Additional studies are needed to further characterize this population given the increase in marijuana use.
... THC also induces CB 1 and CB 2 activation that has been shown to activate platelet aggregation via increased platelet Glycoprotein IIa/IIIb and P-selectin expression [40,41]. Additionally, THC associated increase in inflammation leads to production of 2-Arachidonoylglycerol (2-AG) that serves as a precursor Arachidonic Acid [40]. ...
... THC also induces CB 1 and CB 2 activation that has been shown to activate platelet aggregation via increased platelet Glycoprotein IIa/IIIb and P-selectin expression [40,41]. Additionally, THC associated increase in inflammation leads to production of 2-Arachidonoylglycerol (2-AG) that serves as a precursor Arachidonic Acid [40]. Initial effects of 2-AG on platelet aggregation begin with Phosphotidylinositol 3 Kinase/AKT pathway leading to myosin light chain kinase phosphorylation and subsequent actin polymerization that result in conformational changes in platelet structure. ...
Article
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Cannabis use in the US is rising with increased legalization. It has been noted that there is a five-fold increase risk of Myocardial Infarctions (MI) in the first hour after cannabis use. Traditional risk factors for MI include diabetes, hypertension and dyslipidemia. The rising use of cannabis may have ushered in an additional MI risk factor to be added to the list; that is cannabis. In this review, we discuss the growing use of cannabis and potential link with MI, highlighting the common pathogenic hypotheses linking these risk factors.
... Signalling via CB1 and CB2 receptors differentially affects vascular inflammation. Stimulation of vascular and cardiac CB1 receptors contributes to pathophysiology of various cardiovascular diseases via promotion of oxidative and nitrosative stress, activation of mitogen-activated protein kinase and cell demise [66, [211][212][213][214]. In contrast, a wealth of experimental data indicate that stimulation of CB2 receptors displays cardioprotective effect [215][216][217][218], reduces cerebral ischemic injury [219,220], limits inflammation, oxidative/ nitrosative stress, cell demise [221], progression of atherosclerosis [3,214,[222][223][224], prevents nephrotoxicity [225]. ...
... Stimulation of vascular and cardiac CB1 receptors contributes to pathophysiology of various cardiovascular diseases via promotion of oxidative and nitrosative stress, activation of mitogen-activated protein kinase and cell demise [66, [211][212][213][214]. In contrast, a wealth of experimental data indicate that stimulation of CB2 receptors displays cardioprotective effect [215][216][217][218], reduces cerebral ischemic injury [219,220], limits inflammation, oxidative/ nitrosative stress, cell demise [221], progression of atherosclerosis [3,214,[222][223][224], prevents nephrotoxicity [225]. An increased expression level of CB2 receptors in the cardiovascular system under pathophysiological conditions, such as inflammation and tissue injury, is considered to represent a compensatory protective mechanism [216,[226][227][228]. ...
Chapter
Cannabinoids influence cardiovascular variables in health and disease via multiple mechanisms. The chapter covers the impact of cannabinoids on cardiovascular function in physiology and pathology and presents a critical analysis of the proposed signalling pathways governing regulation of cardiovascular function by endogenously produced and exogenous cannabinoids. We know that endocannabinoid system is overactivated under pathological conditions and plays both a protective compensatory role, such as in some forms of hypertension, atherosclerosis and other inflammatory conditions, and a pathophysiological role, such as in disease states associated with excessive hypotension. This chapter focuses on the mechanisms affecting hemodynamics and vasomotor effects of cannabinoids in health and disease states, highlighting mismatches between some studies. The chapter will first review the effects of marijuana smoking on cardiovascular system and then describe the impact of exogenous cannabinoids on cardiovascular parameters in humans and experimental animals. This will be followed by analysis of the impact of cannabinoids on reactivity of isolated vessels. The article critically reviews current knowledge on cannabinoid induction of vascular relaxation by cannabinoid receptor-dependent and –independent mechanisms and dysregulation of vascular endocannabinoid signaling in disease states.
... THC also induces CB 1 and CB 2 activation that has been shown to activate platelet aggregation via increased platelet Glycoprotein IIa/IIIb and P-selectin expression [22,23]. Additionally, THC associated increase in inflammation leads to production 2-Arachidonoylglycerol (2AG) that serves as a precursor Arachidonic Acid [22]. ...
... THC also induces CB 1 and CB 2 activation that has been shown to activate platelet aggregation via increased platelet Glycoprotein IIa/IIIb and P-selectin expression [22,23]. Additionally, THC associated increase in inflammation leads to production 2-Arachidonoylglycerol (2AG) that serves as a precursor Arachidonic Acid [22]. Initial effects of 2-AG on platelet aggregation begin with Phosphotidylinositol 3 Kinase/AKT pathway leading to myosin light chain kinase phosphorylation and subsequent actin polymerization that result in conformational changes in platelet structure. ...
Article
Full-text available
Background: Marijuana use has been increasingly legalized in the United States resulting in substantial rise in the number of users especially in the younger populations. While our group and others had described various metabolic effects of this drug, little is known about its association with acute myocardial infarction. Objective: To present a series of 8 patients with 10 events of ST-elevation MI (STEMI) associated with marijuana use; highlighting their demographic, clinical presentation, laboratory results and angiographic characteristics. Methods: Retrospective chart review of patients with STEMI presenting to our inner city hospital Coronary Care Unit over a period of 4 years (December 2013-April 2017). Results: Of the 10 case subjects studied who presented with chest pain, EKG evidence of STEMI with cannabis use, mean age at presentation was 40.1 ± 9.7 (years) SD, ranging from 26 to 59 years old. There were 9 males and one female, of them, 8 were Black, 2 Hispanic and 1 White. Of the 10 cases, 3 (30%) had no known cardiovascular disease (CVD) risk factors (RF) on admission, 1 patient had 3 RF, 4 patients had 2 RF and 2 had 1 CVD RF, which included age, diabetes mellitus type 2 (DM2), hypertension, dyslipidemia, smoking, and family history of premature coronary heart disease. Troponin I (cTnI) peak mean level was 93.5 ± 34.35 ng/ml, range 7.86 - 358.0 ng/ml. All patients had angiographic evidence of obstructive coronary angiography. Conclusion: In our study, marijuana use is associated with ST-elevation MI in largely minority population, occurring at a relatively younger age with half of the cases either low risk or CVD risk free. Additional studies are needed to further characterize this population given the increase in marijuana use.
... Even though search of innovative targets for atherosclerosis treatment appears to hold promises, statins remain the more effective pharmacological compounds for clinical management, despite their unwanted side effects and significant residual cardiovascular risk [8]. In the last decade, solid evidence has pointed to the two main receptors that bind to and mediate the biological activity of exogenous (plant-derived or synthetic) cannabinoids and of their endogenous counterparts (endocannabinoids), namely type-1 and type-2 cannabinoid receptors (CB 1 R and CB 2 R), as relevant players in atherosclerosis, endowed with pro-atherogenic [9,10] and anti-atherogenic effects respectively [11][12][13][14]. Yet, the actual role of CB 1 R and CB 2 Rremains controversial, because conflicting results have been reported by independent investigators [15,16]. ...
Article
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The G protein-coupled receptor GPR55 has been proposed as a new cannabinoid receptor associated with bone remodelling, nervous system excitability, vascular homeostasis as well as in several pathophysiological conditions including obesity and cancer. However, its physiological role and underlying mechanism remain unclear. In the present work, we demonstrate for the first time its presence in human macrophages and its increased expression in ox-LDL-induced foam cells. In addition, pharmacological activation of GPR55 by its selective agonist O-1602 increased CD36- and SRB-I-mediated lipid accumulation and blocked cholesterol efflux by downregulating ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, as well as enhanced cytokine- and pro-metalloprotease-9 (pro-MMP-9)-induced proinflammatory responses in foam cells. Treatment with cannabidiol, a selective antagonist of GPR55, counteracted these pro-atherogenic and proinflammatory O-1602-mediated effects. Our data suggest that GPR55 could play deleterious role in ox-LDL-induced foam cells and could be a novel pharmacological target to manage atherosclerosis and other related cardiovascular diseases.
... Finally, we also investigated the potential effect of mediators involved, since TNF-α-release induced apoptosis was reported in cardiomyocytes [43,44] via activation of TNF-α-receptor 1 (TNFR1), and TNF-α is also expressed on cardiomyocytes during ischemic stress [45]. For this purpose we applied the endocannabinoid anandamide, which was associated with anti-inflammatory effects while acting on CB2 receptor [46,47]. The application of anandamide led to a significant suppression of TNF-α production in WT-M1-MOs under hypoxic conditions, and thereby revealed a CB2 receptor-dependent effect on the M1-MOs as well. ...
... Finally, we also investigated the potential effect of mediators involved, since TNF-α-release induced apoptosis was reported in cardiomyocytes [43,44] via activation of TNF-α-receptor 1 (TNFR1), and TNF-α is also expressed on cardiomyocytes during ischemic stress [45]. For this purpose we applied the endocannabinoid anandamide, which was associated with anti-inflammatory effects while acting on CB2 receptor [46,47]. The application of anandamide led to a significant suppression of TNF-α production in WT-M1-MOs under hypoxic conditions, and thereby revealed a CB2 receptor-dependent effect on the M1-MOs as well. ...
... Endocannabinoids are emerging as unique mediators of organ homeostasis, and this concept also applies to the cardiovascular system. In fact, experimental evidence indicates their involvement in the regulation of systemic blood pressure (19) and cardiac output (2) and in atherosclerosis (20). Herein, we demonstrate that AEA mediates hypoxic pulmonary vasoconstriction and is also involved in pulmonary hypertension via its degradation to FAAH-dependent metabolites. ...
Article
Endocannabinoids are important regulators of organ homeostasis. Although their role in systemic vasculature has been extensively studied, their impact on pulmonary vessels remains less clear. Herein, we show that the endocannabinoid anandamide (AEA) is a key mediator of hypoxic pulmonary vasoconstriction (HPV) via fatty acid amide hydrolase (FAAH)-dependent metabolites. This is underscored by the prominent vasoconstrictive effect of AEA on pulmonary arteries and strongly reduced HPV in FAAH(-/-) mice and wild-type mice upon pharmacological treatment with FAAH inhibitor URB597. In addition, mass spectrometry measurements revealed a clear increase of AEA and the FAAH-dependent metabolite arachidonic acid in hypoxic lungs of wild-type mice. We have identified pulmonary vascular smooth muscle cells as the source responsible for hypoxia-induced AEA generation. Moreover, either FAAH(-/-) mice or wild-type mice treated with FAAH inhibitor URB597 are protected against hypoxia-induced pulmonary hypertension and the concomitant vascular remodeling in the lung. Thus, the AEA/FAAH pathway is an important mediator of HPV and is involved in the generation of pulmonary hypertension.
... There is increasing experimental evidence for modulation of endocannabinoid levels, receptors and related enzymes of the biosynthesis and degradation in different inflammatory conditions 24 . Recent studies suggest that up-regulation of anandamide levels may be feasible pharmacological strategies to limit inflammatory organ injury. ...
Article
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Aims: The aim of this study was to investigate the relationship between selected symptoms of chronic heart failure (myocardial infarction, plasma cholesterol level) and single nucleotide polymorphisms (SNPs) in the FAAH and CNR1 genes. Methods: A case - control study involving 155 patients with chronic heart failure and 169 age- and sex-matched healthy subjects. We detected SNPs 385 C/A (rs324420) in the FAAH and 1359 G/A (rs1049353) in the CNR1 genes using the polymerase chain reaction and restriction analysis. Genotype and allele frequencies were compared between patients and controls as well as between patients with and without myocardial infarction. Results: No significant differences in genotype or allelic frequencies between patients and controls were found (P > 0.05). Carriers of the FAAH A allele had a 2.37-fold increase in the risk of myocardial infarction (odds ratio 2.37, 95% confidence interval 1.36-6.93, P = 0.01). Homozygous carriers of genotype AA of CNR1 SNP 1359 had significantly higher plasma cholesterol levels than carriers of GG and GA genotypes in patients (P = 0.04). Conclusions: The study results suggest a role for allele A of the FAAH 385 variant as a risk factor for myocardial infarction. Genotype AA of CNR1 1359 variant probably affects plasma cholesterol levels. Pharmacological intervention in this system could modify the therapeutic approach to certain cardiovascular disorders.
... In addition to their well-known psychotropic effects, cannabinoids exert immunosuppressive and anti-inflammatory effects, leading to the suggestion that cannabinoids may prove beneficial in the treatment of inflammatory disorders [3][4][5][6] and atherosclerosis [7][8][9][10][11][12]. Cannabinoids produce their effects primarily through binding of two G-protein coupled receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). ...
Article
Purpose: WIN55,212-2, a potent synthetic agonist of cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), reduces atherosclerosis in apolipoprotein E (ApoE) null mice. Although pharmacologic evidence suggests the anti-atherosclerotic effects of WIN55,212-2 are mediated via CB2, this remains to be confirmed by genetic studies. Therefore, in this study, we investigated the effects of WIN55,212-2 on development of atherosclerosis in low-density lipoprotein receptor (Ldlr) null mice with and without homozygous deletion of the CB2 gene. Methods: After 6 weeks on an atherogenic diet, groups of CB2(+/+) and CB2(-/-) Ldlr-null mice received a daily intraperitoneal injection of WIN55,212-2 or vehicle. After two weeks, plasma lipid levels and atherosclerosis in the aortic root were quantified. Results: Plasma cholesterol and triglyceride levels did not differ between CB2(+/+) and CB2(-/-) mice and WIN55,212-2 had no effect on total cholesterol levels in either genotype. However, triglyceride levels in both CB2(+/+) and CB2(-/-) mice were significantly lowered by WIN55,212-2. The size of aortic root lesions did not differ significantly between CB2(+/+) and CB2(-/-) mice with or without WIN55,212-2 treatment. However, WIN55,212-2 treatment significantly lowered lesional macrophage accumulation in CB2(+/+) mice, and lesional smooth muscle content in both CB2(+/+) and CB2(-/-) mice. Lesional apoptosis was also greater in CB2(+/+) mice compared to CB2(-/-)mice, and only reduced by WIN55,212-2 in CB2(+/+) mice. Collagen content and elastin fiber fragmentation were unaffected by genotype or WIN55,212-2. Conclusions: WIN55,212-2 treatment does not alter lesion size in Ldlr null-mice, but does modify lesion cellularity via CB2-dependent and CB2-independent mechanisms.
... Therefore, the local concentration of 2-AG in various niches may be an important determinant of disease development. For example, endocannabinoids released from endothelial cells, macrophages and platelets play a critical role during atherogenesis and can partially contribute to its clinical manifestations 5 . ...
Article
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ABSTRACT The profiles of serine hydrolases in human and mouse macrophages are similar yet different. For instance, human macrophages express high levels of carboxylesterase 1 (CES1), whereas mouse macrophages have minimal amounts of the orthologous murine CES1. On the other hand, both species' macrophages exhibit limited expression of the canonical 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, MAGL. Our previous study showed carboxylesterase 1 (CES1) was partly responsible for the hydrolysis of 2-AG (50%) and prostaglandin glyceryl esters (PG-Gs) (80-95%) in human THP1 monocytes/macrophages. However, MAGL and other endocannabinoid hydrolases, FAAH, ABHD6 and ABHD12, did not have a role because of either limited or no expression. Thus, another enzyme was hypothesized to be responsible for the remaining 2-AG hydrolysis activity following chemical inhibition and immunodepletion of CES1 (previous study) or CES1 gene knockdown (this study). Here we identified two candidate serine hydrolases in THP1 cell lysates by activity-based protein profiling (ABPP)-MudPIT and western blotting: cathepsin G and palmitoyl protein thioesterase 1 (PPT1). Both proteins exhibited similar electrophoretic properties to a serine hydrolase in THP1 cells detected by gel-based ABPP at 31-32 kDa; however, only PPT1 exhibited lipolytic activity and hydrolyzed 2-AG in vitro. Interestingly, PPT1 was highly expressed in THP1 cells but was significantly less reactive than cathepsin G toward the activity-based probe, fluorophosphonate-biotin. KIAA1363, another serine hydrolase, was also identified in THP1 cells but did not have significant lipolytic activity. On the basis of chemoproteomic profiling, immunodepletion studies and chemical inhibitor profiles, we estimated that PPT1 contributed 32-40% of 2-AG hydrolysis activity in the THP1 cell line. In addition, pure recombinant PPT1 catalyzed the hydrolysis of 2-AG, PGE2-G and PGF2α-G, although the catalytic efficiency of 2-AG hydrolysis by PPT1 was ~10-fold lower than CES1's. PPT1 was also insensitive to several chemical inhibitors that potently inhibit CES1, such as organophosphate poisons and JZL184. This is the first report to document the expression of PPT1 in a human monocyte/macrophage cell line and to show PPT1 can hydrolyze the natural substrates 2-AG and PG-Gs. These findings suggest that PPT1 may participate in endocannabinoid metabolism within specific cellular contexts, and highlights the functional redundancy often exhibited by enzymes involved in lipid metabolism.
... The peripheral cannabinoid receptor (CB2-R) has been reported to be expressed in advanced human and murine atherosclerotic plaque (18). CB2-R has an important immunomodulatory function in atherosclerosis which is mediated by endogenous cannabinoids (19). Activation of CB2-R by a synthetic agonist led to a decrease of the amount of atherosclerosis (18). ...
Article
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Single fast spin echo scans covering limited time frames are mostly used for contrast-enhanced MRI of atherosclerotic plaque biomarkers. Knowledge on inter-scan variability of the normalized enhancement ratio of plaque (NER(plaque)) and relation between NER(plaque) and gadolinium content for inversion-recovery fast spin echo is limited. Study aims were: evaluation of (1) timing of MRI after intravenous injection of cannabinoid-2 receptor (CB2-R) (expressed by human and mouse plaque macrophages) targeted micelles; (2) inter-scan variability of inversion-recovery fast spin echo and fast spin echo; (3) relation between NER(plaque) and gadolinium content for inversion-recovery fast spin echo and fast spin echo. Inversion-recovery fast spin echo/fast spin echo imaging was performed before and every 15 min up to 48 h after injection of CB2-R targeted or control micelles using several groups of mice measured in an interleaved fashion. NER(plaque) (determined on inversion-recovery fast spin echo images) remained high (∼2) until 48 h after injection of CB2-R targeted micelles, whereas NER(plaque) decreased after 36 h in the control group. The inter-scan variability and relation between NER(plaque) and gadolinium (assessed with inductively coupled plasma- mass spectrometry) were compared between inversion-recovery fast spin echo and fast spin echo. Inter-scan variability was higher for inversion-recovery fast spin echo than for fast spin echo. Although gadolinium and NER(plaque) correlated well for both techniques, the NER of plaque was higher for inversion-recovery fast spin echo than for fast spin echo. In mice injected with CB2-R targeted micelles, NER(plaque) can be best evaluated at 36-48 h post-injection. Because NER(plaque) was higher for inversion-recovery fast spin echo than for fast spin echo, but with high inter-scan variability, repeated inversion-recovery fast spin echo imaging and averaging of the obtained NER(plaque) values is recommended.
... However, a number of other ligands have been identified, which express high selectivity for CB 2 (Pertwee 2006). Using these reagents, it has been shown that activation of CB 2 receptor can regulate both innate and adaptive immunity including the ability to suppress anti-cancer responses (McKallip et al. 2005;Zhu et al. 2000) and host defenses against pneumonia (Klein et al. 2000;Newton et al. 2009;Shay et al. 2003), promote apoptosis of antigen presenting cells and T cells (Do et al. 2004;McKallip et al. 2002), alter cytokine production and antibody isotype switching (Agudelo et al. 2008;Cencioni et al. 2010;Srivastava et al. 1998;Yuan et al. 2002), modulate the infectivity and replication of HIV virus (Gorantla et al. 2010;Roth et al. 2005), regulate the inflammatory aspects of atherosclerosis (Mach and Steffens 2008), and play a role in several autoimmune diseases (Malfait et al. 2000;Sipe et al. 2005). This body of work has lead to considerable interest in understanding the role that endogenous cannabinoids have in the immune system and in developing CB 2 -selective therapies (Klein 2005;Mackie 2006). ...
Article
mRNA encoding for the CB(2) cannabinoid receptor is expressed by many subsets of human peripheral blood leukocytes (PBL), but little is known about the resulting protein expression and function. Employing clones from the A549 and 293T cell lines that were constructed to express both full-length human CB(2) and GFP, we developed a flow cytometry assay for characterizing CB(2) protein expression. A monoclonal antibody directed against human CB(2) selectively stained the surface of transduced but not parental cell lines. When cells were fixed and permeabilized, imaging flow cytometry identified large stores of intracellular protein. Total cellular staining for CB(2) corresponded closely with the level of GFP expression. When exposed to Δ(9)-tetrahydrocannabinol, CB(2)-expressing cells internalized cell surface CB(2) receptors in a time- and dose-dependent manner. Applying these approaches to human PBL, CB(2) protein was identified on the surface of human B cells but not on T cells or monocytes. In contrast, when PBL were fixed and permeabilized, intracellular CB(2) expression was readily detected in all three subsets by both conventional and imaging flow cytometry. Similar to the protein expression pattern observed in fixed and permeabilized PBL, purified B cells, T cells, and monocytes expressed relatively equal levels of CB(2) mRNA by quantitative real-time RT-PCR. Our findings confirm that human PBL express CB(2) protein but that its distribution is predominantly intracellular with only B cells expressing CB(2) protein at the extracellular membrane. The differential role of intracellular and extracellular CB(2) receptors in mediating ligand signaling and immune function remains to be determined.
... Despite this effort, little is known about how cannabinoids regulate monocyte migration, an early and fundamental step of immune response implementation. Endogenous cannabinoids (endocannabinoids, eCB) are lipids that activate cannabinoid receptors expressed by many cell types (Mach and Steffens 2008). The two primary eCBs, arachidonoylethanolamine (AEA or anandamide) and 2-arachidonoyl glycerol (2-AG), are produced by many cell types, including endothelial cells and T cells (Rossi et al. 2010; Zhang et al. 2011; Huang et al. 2010). ...
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This study evaluates the migratory potential of monocytes isolated from two groups of human subjects: naïve and non-naïve to Cannabis. Phytocannabinoids (pCB), the bioactive agents produced by the plant Cannabis, regulate the phenotype and function of immune cells by interacting with CB(1) and CB(2) receptors. It has been shown that agents influencing the phenotype of circulating monocytes influence the phenotype of macrophages and the outcome of immune responses. To date, nothing is known about the acute and long-term effects of pCB on human circulating monocytes. Healthy subjects were recruited for a single blood draw. Monocytes were isolated, fluorescently labeled and their migration quantified using a validated assay that employs near infrared fluorescence and modified Boyden chambers. CB(1) and CB(2) receptor mRNA expression was quantified by qPCR. Monocytes from all subjects (n = 10) responded to chemokine (c-c motif) ligand 2 (CCL2) and human serum stimuli. Acute application of pCB significantly inhibited both the basal and CCL2-stimulated migration of monocytes, but only in subjects non-naïve to Cannabis. qPCR analysis indicates that monocytes from subjects non-naïve to Cannabis express significantly more CB(1) mRNA. The phenotype of monocytes isolated from subjects non-naïve to Cannabis is significantly different from monocytes isolated from subjects naïve to Cannabis. Only monocytes from subjects non-naïve to Cannabis respond to acute exposure to pCB by reducing their overall migratory capacity. Our study suggests that chronic exposure to Cannabis affects the phenotype of circulating monocytes and accordingly could influence outcome of inflammatory responses occurring in injured tissues.
... CB2 receptors are present in the immune system (lymphoid tissues such as spleen, thymus and lymph nodes, as well as circulating lymphocytes and macrophages and microglia). Their function remains somewhat enigmatic, although they are expressed in atherosclerotic lesions and CB2 agonists have anti-atherosclerotic effects [3]. ...
... Cannabinoids, endogenous and synthetic, have complex cardiovascular actions through the activation of CB1 receptors (vascular and myocardial) (Steinberg et al., 2007). The decline of cardiac function associated with age and the changes in inflammation genes expression, nitrative stress and apoptosis in rats FAAH -/-compared with wild type rats was analyzed Mach & Steffens, 2008). The authors found that increased levels of anandamide in FAAH -/-rats have a protective effect, which is consistent with the protective role of cannabinoids in inflammatory disorders, such as atherosclerosis. ...
... Activation of the CB 1 receptor, with agonists such as anandamide, induces vasorelaxation [33,34] and a decrease in the blood pressure in normotensive and hypertension models [35,36]. Blockade of the CB 1 receptor decreases the atherosclerosis risk while activation of the CB 2 receptor decreases the progression of the atherosclerosis acting as a cardioprotective agent [37][38][39][40][41]. Furthermore, increased CB 1 receptor expression has been associated with vascular smooth muscle cell proliferation and atherosclerosis [42,43]. ...
Article
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ZnO nanoparticles (ZnONPs) have been shown to have therapeutic potential in some diseases such as diabetes and cancer. However, concentration-dependent adverse effects have also been reported. Studies which evaluate the effects of ZnONPs on the cardiovascular system are scarce. This study aimed to evaluate the cardiovascular effects of a low dose of ZnONPs administered chronically in healthy rats. Changes in dyslipidemia biomarkers, blood pressure, aortic wall structure, vascular contractility, and expression of cannabinoid receptors in the aorta wall were evaluated. Healthy rats were divided into two groups: control or treated (one, two, and three months). The treated rats received an oral dose of 10 mg/kg/day. The results showed that treatment with ZnONPs induced dyslipidemia from the first month, increasing atherosclerosis risk, which was confirmed by presence of atherosclerotic alterations revealed by aorta histological analysis. In in vitro assays, ZnONPs modified the aorta contractile activity in response to the activation of cannabinoid receptors (CB1 and CB2). The expression of CB1 and CB2 was modified as well. Moreover, ZnONPs elicited an increase in blood pressure. In conclusion, long-time oral administration of ZnONPs induce dyslipidemia and atherosclerosis eliciting alterations in aorta contractility, CB1 and CB2 receptors expression, and an increase in blood pressure in healthy rats.
... For this reason, the need to continue studies on pharmacological agents preventing and/or treating IRI remains evident. There has also long been interest in the use of cannabis products in the treatment of various medical conditions, including pain [47], multiple sclerosis [48], Huntington's disease [49], stroke [50], atherosclerosis [51,52], inflammatory bowel diseases [53], renal fibrosis [54] and cancer [55]. On the other hand, chronic inflammatory disease of the artery wall and endothelial dysfunction has been proposed as a key mechanism of CV risk [1,6,56,57], and the endocannabinoid system is also thought to be an important signalling pathway in the cardiovascular system [58]. ...
Article
Background: Ischemia/reperfusion (I/R) is a pivotal mechanism of organ injury during clinical stetting for example for cardiopulmonary bypasses. The generation of reactive oxygen species (ROS) during I/R induces oxidative stress that promotes endothelial dysfunction, DNA dissociation and local inflammation. In turn, those processes induce cytokine release, resulting in damage to cellular structures and cell death. One of the major psychoactive compounds of Cannabis is delta-9-tetrahydrocannabinol (Δ9-THC), which is known as an anti-inflammatory mediator. Our research aimed to test if Δ9-THC may be protective in the treatment of cardiovascular system dysfunction arising from I/R heart injury. Methods: Two experimental models were used: isolated rat hearts perfused with the Langendorff method and human cardiac myocytes (HCM) culture. Rat hearts and HCM underwent ex vivo/chemical in vitro I/R protocol with/without Δ9-THC treatment. The following parameters were measured: cell metabolic activity, morphology changes, cell damage as lactate dehydrogenase (LDH) activity, ceramide kinase (CERK) activity, ROS level, total antioxidant capacity (TAC) and heart hemodynamic parameters. Results: Δ9-THC protected the heart, as evidenced by the improved recovery of cardiac function (p < 0.05, N = 3-6). Cells subjected to I/R showed lower cytoplasmic LDH activity, and 10 μM Δ9-THC treatment reduced cell injury and increased LDH content (p = 0.019, N = 6-9). Morphology changes of HCM-spherical shape, vacuolisation of cytoplasm and swollen mitochondria-were inhibited due to Δ9-THC treatment. I/R condition affected cell viability, but 10 μM Δ9-THC decreased the number of dead cells (p = 0.005, N = 6-9). The total level of CERK was lower in the I/R group, reflecting oxidative/nitrosative stress changes. The administration of Δ9-THC effectively increased the production of CERK to the level of aerobic control (p = 0.028, N = 6-9). ROS level was significantly decreased in I/R cells (p = 0.007, N = 6-8), confirming oxidative stress, while administration of 10 μM Δ9-THC enhanced TAC in cardiomyocytes subjected to I/R (p = 0.010, N = 6-8). Conclusions: Δ9-THC promotes the viability of cardiomyocytes, improves their metabolic activity, decreases cell damage and restores heart mechanical function, serving as a cardioprotective. We proposed the use of Δ9-THC as a cardioprotective drug to be, administered before onset of I/R protocol.
... Plant and animal cannabinoids carry out their functions through receptors mediating mechanisms via cannabinoid receptors (CB1R and CB2R) interactions [4,5]. In humans, an array of cannabinoid-mediated processes, termed the endogenous cannabinoid system (ECS), modulates various physiological and pathophysiological activities that span all body organ systems including neurological [6], intestinal [7], pregnancy [8], and pathological processes such as immunity [9], irritable bowel disease [10], atherosclerosis [11], and hepatic disorders [12]. However, the impact of plant cannabinoids contained in cannabis plant on diverse ECS-mediated and ECS-regulated processes remain unclear. ...
Article
Background: The endogenous cannabinoid system modulates many brain-gut and gut-brain physiologic pathways, which are postulated to be dysfunctional in irritable bowel syndrome (IBS). Herein, we examine the relationship between cannabis use disorder (CUD) and having IBS. Patients and methods: After selecting patients aged 18 years and above from the 2014 Nationwide Inpatient Survey, we used the International Classification of Diseases, 9th ed. codes to identify individuals with CUD, IBS, and the established risk factors for IBS. We then estimated the crude and adjusted odds ratios of having a diagnosis of IBS with CUD and assessed for the interactions of CUD with other risk factors (SAS 9.4). We confirmed our findings in two ways: conducting a similar analysis on a previous Nationwide Inpatient Survey data (2012); and using a greedy algorithm to design a propensity-scored case-control (1 : 10) study, approximating a pseudorandomized clinical trial. Results: Out of 4 709 043 patients evaluated, 0.03% had a primary admission for IBS and 1.32% had CUD. CUD was associated with increased odds of IBS [adjusted odds ratio: 2.03; 95% confidence interval (CI): 1.53-2.71]. CUD was related to higher odds for IBS among males compared with females (3.48; 1.98-6.12 vs. 1.48; 0.88-2.50), and Hispanics and Caucasians compared with Blacks (5.28; 1.77-15.76, 1.80; 1.02-3.18 vs. 1.80; 0.65-5.03). On propensity-matching, CUD was associated with 80% increased odds for IBS (1.82; 1.27-2.60). Conclusion: Our findings suggest that CUD is significantly associated with IBS among the general population. Males, Caucasians, and Hispanics might be more impacted by CUD associated IBS. Additional biomedical studies are required to elucidate this relationship.
... The endocannabinoid system is an integral regulator of vascular inflammation and atherogenesis (reviewed by [18]); [14]. While the role of anandamide in atherosclerosis has already been focus for several mechanistic studies, no basic research study has examinined the causal impact of 2-AG on vascular inflammation and atherogenesis in vivo yet. ...
Article
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Background: The endocannabinoid 2-arachidonoylglycerol (2-AG) is a known modulator of inflammation. Despite its high concentration in vascular tissue, the role of 2-AG in atherogenesis has not yet been examined. Methods: ApoE-deficient mice were sublethally irradiated and reconstituted with bone marrow from mice with a myeloid-specific knockout of the 2-AG synthesising enzyme diacylglycerol lipase α (Dagla) or control bone marrow with an intact 2-AG biosynthesis. After a cholesterol-rich diet for 8 weeks, plaque size and plaque morphology were examined in chimeric mice. Circulating inflammatory cells were assessed by flow cytometry. Aortic tissue and plasma levels of endocannabinoids were measured using liquid chromatography-multiple reaction monitoring. Results: Mice with Dagla-deficient bone marrow and circulating myeloid cells showed a significantly reduced plaque burden compared to controls. The reduction in plaque size was accompanied by a significantly diminished accumulation of both neutrophil granulocytes and macrophages in atherosclerotic lesions of Dagla-deficient mice. Moreover, CB2 expression and the amount of oxidised LDL within atherosclerotic lesions was significantly reduced. FACS analyses revealed that levels of circulating inflammatory cells were unaltered in Dagla-deficient mice. Conclusions: Myeloid synthesis of the endocannabinoid 2-AG appears to promote vascular inflammation and atherogenesis. Thus, myeloid-specific disruption of 2-AG synthesis may represent a potential novel therapeutic strategy against atherosclerosis.
... 21−24 However, eCBs have also been shown to exert proinflammatory effects in the context of atherosclerosis and allergic inflammation. 25,26 Thus, the homeostatic and pathophysiological actions exerted by the eCB system are complex and several data gaps exist, particularly in settings of environmental toxicant exposures. ...
Article
Chlorpyrifos (CPF) is an organophosphate (OP) pesticide that causes acute toxicity by inhibiting acetylcholinesterase (AChE) in the nervous system. However, endocannabinoid (eCB) metabolizing enzymes in brain of neonatal rats are more sensitive than AChE to inhibition by CPF, leading to increased levels of eCBs. Because eCBs are immunomodulatory molecules, we investigated the association between eCB metabolism, lipid mediators, and immune function in adult and neonatal mice exposed to CPF. We focused on lung effects because epidemiologic studies have linked pesticide exposures to respiratory diseases. CPF was hypothesized to disrupt lung eCB metabolism and alter lung immune responses to lipopolysaccharide (LPS), and these effects would be more pronounced in neonatal mice due to an immature immune system. We first assessed the biochemical effects of CPF in adult mice (≥8 weeks old) and neonatal mice after administering CPF (2.5 mg/kg, oral) or vehicle for 7 days. Tissues were harvested 4 h after the last CPF treatment and lung microsomes from both age groups demonstrated CPF-dependent inhibition of carboxylesterases (Ces), a family of xenobiotic and lipid metabolizing enzymes, whereas AChE activity was inhibited in adult lungs only. Activity-based protein profiling (ABPP)-mass spectrometry of lung microsomes identified 31 and 32 individual serine hydrolases in neonatal lung and adult lung, respectively. Of these, Ces1c/Ces1d/Ces1b isoforms were partially inactivated by CPF in neonatal lung, whereas Ces1c/Ces1b and Ces1c/BChE were partially inactivated in adult female and male lungs, respectively, suggesting age- and sex-related differences in their sensitivity to CPF. Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) activities in lung were unaffected by CPF. When LPS (1.25 mg/kg, i.p.) was administered following the 7-day CPF dosing period, little to no differences in lung immune responses (cytokines and immunophenotyping) were noted between the CPF and vehicle groups. However, a CPF-dependent increase in the amounts of dendritic cells and certain lipid mediators in female lung following LPS challenge was observed. Experiments in neonatal and adult Ces1d - /- mice yielded similar results as wild type mice (WT) following CPF treatment, except that CPF augmented LPS-induced Tnfa mRNA in adult Ces1d - /- mouse lungs. This effect was associated with decreased expression of Ces1c mRNA in Ces1d - /- mice versus WT mice in the setting of LPS exposure. We conclude that CPF exposure inactivates several Ces isoforms in mouse lung and, during an inflammatory response, increases certain lipid mediators in a female-dependent manner. However, it did not cause widespread altered lung immune effects in response to an LPS challenge.
... An increasing number of studies reported on the crucial role of CB2 in inflammatory processes [40,41]. We found a 2-fold increase with statistical significance of CB2 mRNA in carotid plaques than normal arteries. ...
Article
Introduction: Endarterectomized human atherosclerotic plaques are a valuable basis for gene expression studies to disclose novel imaging biomarkers and therapeutic targets, such as the cannabinoid receptor type 2 (CB2). In this work, CB2 is expressed on activated immune cells, which are abundant in inflamed plaques. We evaluated the CB2-specific radiotracer [(11)C]RS-016 for imaging vascular inflammation in human and mouse atherosclerotic lesions. Methods: The differential gene expression of microscopically classified human carotid plaques was evaluated using quantitative polymerase chain reaction. In addition, CB2 expression levels in human plaques were investigated by in vitro autoradiography. As an appropriate animal model we used apolipoprotein E knockout mice (ApoE KO) with shear stress-induced atherosclerosis to evaluate CB2 levels in vivo. Positron emission tomography (PET) was performed with both the CB2 radioligand [(11)C]RS-016 and the metabolic radiotracer [(18)F]fluorodeoxyglucose ([(18)F]FDG) at various time points. Retrospectively, carotids were dissected for histopathology and gene expression analysis. Results: We identified 28 human genes differentially expressed in atherosclerotic plaques compared to normal arteries of which 12 were upregulated preferentially in vulnerable plaques. The latter group included members of matrix metalloproteinase family and the T-lymphocyte activation antigens CD80 and CD86. CB2 was upregulated by 2-fold in human atherosclerotic plaques correlating with CD68 expression levels. Specific in vitro binding of [(11)C]RS-016 was predominantly observed to plaques. In vivo PET imaging of ApoE KO mice revealed accumulation of [(11)C]RS-016 and [(18)F]FDG in atherosclerotic plaques. Development of advanced plaques with elevated CB2 and CD68 levels were found in vitro in ApoE KO mice resembling human vulnerable plaques. Conclusion: We identified human genes associated with plaque vulnerability, which potentially could serve as novel imaging or therapeutic targets. The CB2-specific radiotracer [(11)C]RS-016 detected human plaques by in vitro autoradiography and accumulated in vivo in plaques of ApoE KO mice, however not exclusively in vulnerable plaques.
... It is shown that THC acting on CB receptors leads to increased platelet aggregation through increased platelet P-selectin and glycoprotein IIa/IIIb expression. Furthermore, THC leads to the formation of 2arachidonoylglycerol (2-AG), which is a precursor for arachidonic acid [26]. Initially, the effects of 2-AG on the aggregation of platelets start with Phosphatidylinositol 3 Kinase/AKT pathway. ...
Article
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Legalizing cannabis use in various states in the United States has caused increased substance abuse, mostly among young people. There are very little data focussing on marijuana use and myocardial infarction (MI) incidence. The objective of the study is to analyze the published papers for cannabis-induced MI and derive a strong relation between cannabis use and MI and understand the pathophysiology. An online search was conducted in PubMed, Google Scholar, and PubMed Central to find relevant publications examining patients who developed MI due to cannabis use. Out of 32 articles that were identified for this review, 17 are case reports, one is a letter to the editor, eight are observational studies, and six are review articles. Many studies have proposed different mechanisms by which cannabis affects the body. Our study shows that marijuana can precipitate MI even if it is used for the first time. Limited data is available to comment on the mortality of patients after cannabis-induced MI. These findings highlight the necessity for public awareness to prevent the ill-effects of cannabis, especially for teenagers and older people
... Endocannabinoids are having minimal role in cardiovascular regulation under normal physiological condition. [12] Atherosclerosis is a chronic inflammatory disease which will progress and having the potential to cause myocardial infarction and stroke. Inflammatory process is evident in every process of atherogenesis from fatty streak to plaque rupture, in both acute and chronic complications of atherosclerosis. ...
Presentation
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Cannabinoids are the organic compounds derived from the flowering top of cannabis plant commonly known as marijuana. Humans' knowledge about the cannabinoids dates back to the period of their own beginnings. These substances have been used by ancient humans for therapeutic and recreational purposes. Considering the lack of acceptable medical use, safety and illicit use, the cultivation of cannabis plant and the use of plant derived compounds was banned in modern history. But the unmet need in the field of treating cancer and neurodegenerative disorders like multiple sclerosis opened the door for the research on cannabinoids. Drugs like nabilone, dronabinol, Sativex have been approved for these indications and Rimonabant, the drug approved for obesity was banned for causing suicidal thoughts and depression. Despite the hide and seek from the researchers, the cannabinoids have been studied in various disorders of CNS, CVS, GIT and Immune system. The growing interest in this field is also due to the better understanding of endogenous cannabinoids system, and its imbalance in disease conditions. In this presentation, the pharmacology of cannabinoids and their therapeutic potential will be discussed under following headings …  Pharmacology of cannabinoids  Endocannabinoid system  Phytocannabinoids  Synthetic analogues  Therapeutic uses Abstract for Subject Review Cannabinoids-Pharmacology and their potential therapeutic applications 1 | P a g e Subject review Cannabinoids-Pharmacology and their potential therapeutic applications  Introduction  Pharmacology of cannabinoids • Phytocannabinoids • Endocannabinoid system • Synthetic analogues  Therapeutic uses
... For instance, it is well established that endocannabinoids and inhibitors of endocannabinoid catabolism exert anti-inflammatory effects in some disease processes such as autoimmune disorders, LPS-induced inflammation, and colitis [1,3,[10][11][12][13][14]17]. On the other hand, endocannabinoids might be more pro-inflammatory in some disease processes such as atherosclerosis [35]. The role that the endocannabinoid system plays in inflammation resolution is even less understood. ...
Article
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Endocannabinoid-metabolizing enzymes are downregulated in response to lipopolysaccharide (LPS)-induced inflammation in mice, which may serve as a negative feedback mechanism to increase endocannabinoid levels and reduce inflammation. Increased plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) and decreased fatty acid amide hydrolase (FAAH) activity in peripheral lymphocytes from individuals diagnosed with Huntington’s disease (HD) suggests that a similar negative feedback system between inflammation and the endocannabinoid system operates in humans. We investigated whether CpG- (unmethylated bacterial DNA) and LPS-induced IL-6 levels in peripheral blood mononuclear cells (PBMCs) from non-HD and HD individuals modulated the activities of endocannabinoid hydrolases monoacylglycerol lipase (MAGL) and carboxylesterase (CES). Baseline plasma IL-6 levels and 2-arachidonoylglycerol (2-AG) hydrolytic activity in PBMC lysates were not different in HD and non-HD individuals. Inhibition of MAGL and CES1 activity in PBMCs using the inhibitors JZL184 and WWL113, respectively, demonstrated that MAGL was the dominant 2-AG hydrolytic enzyme in PBMCs, regardless of disease state. Correlative analyses of 2-AG hydrolytic activity versus enzyme abundance confirmed this conclusion. Flow cytometric analysis of PBMCs showed that MAGL and CES1 were primarily expressed in monocytes and to a lesser extent in lymphocytes. In conclusion, these data suggest that IL-6 did not influence 2-AG hydrolytic activity in human PBMCs; however, monocytic MAGL was shown to be the predominant 2-AG hydrolytic enzyme.
... Plant and animal cannabinoids carry out their functions through receptors mediating mechanisms via cannabinoid receptors (CB1R and CB2R) interactions [4,5]. In humans, an array of cannabinoid-mediated processes, termed the endogenous cannabinoid system (ECS), modulates various physiological and pathophysiological activities that span all body organ systems including neurological [6], intestinal [7], pregnancy [8], and pathological processes such as immunity [9], irritable bowel disease [10], atherosclerosis [11], and hepatic disorders [12]. However, the impact of plant cannabinoids contained in cannabis plant on diverse ECS-mediated and ECS-regulated processes remain unclear. ...
... Atherosclerosis is a chronic inflammatory disease resulting from the accumulation of lipids (such as cholesterol crystals, modified fatty acids, and lysophospholipids) and fibrous elements in the coronary artery and aorta. It is known that VSMCs are closely involved in the development of atherosclerosis [11,154,203]. This disease is particularly associated with the decreased vascular activity of endothelium-derived nitric oxide, which is likely to play an important role in the development of atherosclerosis with aging. ...
Article
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Potassium (K⁺) ion channel activity is an important determinant of vascular tone by regulating cell membrane potential (MP). Activation of K⁺ channels leads to membrane hyperpolarization and subsequently vasodilatation, while inhibition of the channels causes membrane depolarization and then vasoconstriction. So far five distinct types of K⁺ channels have been identified in vascular smooth muscle cells (VSMCs); Ca⁺²‐activated K⁺ channels (BKCa), voltage‐dependent K⁺ channels (KV), ATP‐sensitive K⁺ channels (KATP), inward rectifier K⁺ channels (Kir), and tandem‐two pore K⁺ channels (K2P). The activity and expression of vascular K⁺ channels are changed during major vascular diseases such as hypertension, pulmonary hypertension, hypercholesterolemia, atherosclerosis, and diabetes mellitus. The defective function of K⁺ channels is commonly associated with impaired vascular responses and is likely to become as a result of changes in K⁺ channels during vascular diseases. Increased K⁺ channel function and expression may also help to compensate for increased abnormal vascular tone. There are many pharmacological and genotypic studies which were carried out on the subtypes of K⁺ channels expressed in variable amounts in different vascular beds. Modulation of K⁺ channel activity by molecular approaches and selective drug development may be a novel treatment modality for vascular dysfunction in the future. This review presents the basic properties, physiological functions, pathophysiological and pharmacological roles of the five major classes of K⁺ channels that have been determined in VSMCs. This article is protected by copyright. All rights reserved.
Chapter
The endocannabinoid systems (ECS) is an old and evolutionary well-preserved neurobiologic system controlling some key elements of organ homeostasis. In contrast to its long biologic history, the scientific record of the ECS is very short. Whereas the occurrence of genes for the endocannabinoid receptors has been described in ancient animals reaching at least as far back as the predecessor of tetrapods (amphibians reptiles, birds and mammals), modern science has only very recently demonstrated that the ECS is involved in the regulation of a wide range of essential central and peripheral processes which include metabolism and feeding behavior, inflammatory- and anti-inflammatory immunologic reactions, neurobehavioral changes during stress and anxiety and the regulation of central functions such as cognition and memory. One of the most important roles of the ECS lies in the regulation and orchestration of the central and immunologic stress response to aversive and threatening life conditions. The ECS may therefore have an important function in sustaining human life under the aversive condition of space flights. © 2012 Springer-Verlag Berlin Heidelberg. All rights are reserved.
Chapter
The endocannabinoid system consists of cannabinoid receptors (which mediate the actions of cannabis), their endogenous ligands (endocannabinoids), and the enzymes and proteins associated with their regulation. In brain, the endocannabinoid system, in part, functions to modulate the release of other neurotransmitters via the subtype 1 (CB1) receptor. Abnormalities of CB1 receptor expression or endocannabinoid transmission have been associated with several neuropsychiatric diseases. Subtype 2 (CB2) receptors are found primarily on immune and neuroimmune cells, and are overexpressed in activated microglia and neuroinflammation. Both receptors are of particular interest for biomarker development and therapeutic targets. Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are responsible for the breakdown of endocannabinoids. Growing evidence supports the regulation of endocannabinoids as involved in neuropsychiatric and neuroinflammatory diseases. However, the function of endocannabinoid system components in vivo remains difficult to assess. Therefore, the use of functional imaging techniques, such as positron-emission tomography (PET), may be particularly useful in the assessment and quantification of the endocannabinoid system. This review covers the current understanding of PET imaging that directly targets the endocannabinoid system.
Article
Anandamide (N-arachidonoylethanolamine [AEA]) is one of the main endocannabinoids. Endocannabinoids are implicated in various physiological and pathologic functions, inducing not only nociception but also regeneration and inflammation. The role of the endocannabinoid system in peripheral organs was recently described. The aim of this study was to investigate the effect of AEA on matrix metalloproteinase (MMP)-2 induction in human dental pulp cells (HPC). We examined AEA-induced MMP-2 production and the expression of AEA receptors (cannabinoid [CB] receptor-1, CB2, and transient receptor potential vanilloid-1 [TRPV1]) in HPC by Western blot. MMP-2 concentrations in supernatants were determined by enzyme-linked immunosorbent assay. We then investigated the role of the AEA receptors and mitogen-activated protein kinase in AEA-induced MMP-2 production in HPC. AEA significantly induced MMP-2 production in HPC. HPC expressed all 3 types of AEA receptor (CB1, CB2, and TRPV1). AEA-induced MMP-2 production was blocked by CB1 or TRPV1 antagonists and by small interfering RNA for CB1 or TRPV1. Furthermore, c-Jun N-terminal kinase inhibitor also reduced MMP-2 production. We demonstrated for the first time that AEA induced MMP-2 production via CB1 and TRPV1 in HPC.
Article
Marijuana has been used for thousands of years to affect human health. Dissecting the peripheral effects from the central psychotropic effects has revealed a complex interplay between cannabinoids, endocannabinoids and their receptors. This review examines recent advances in understanding the expression, regulation and utilization of the CB2 receptor. Here we highlight the molecular aspects of the CB2 receptor, CB2 receptor signaling and new ligands for this receptor. We focus in the rest of the review on recent findings in the immune system, the gastrointestinal tract and liver, the brain and the cardiovascular system and airways as examples of areas where new developments in our understanding of the CB2 receptor have occurred. Early studies focused on expression of this receptor under baseline physiologic conditions; however, perturbations such as those that occur during inflammation, ischemia/reperfusion injury and cancer are revealing a critical role for the CB2 receptor in regulating these disease processes amongst others. As a result, the CB2 receptor is an appealing therapeutic target as well as a useful tool for shedding new light on physiological regulatory processes throughout the body.
Article
The discovery of the endocannabinoid system (ECS; comprising of G-protein coupled cannabinoid 1 and 2 receptors, their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing enzymes, triggered an avalanche of experimental studies that have implicated the ECS in a growing number of physiological/pathological functions. They also suggested that modulating ECS activity holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders, obesity/metabolic syndrome, cachexia, chemotherapy-induced nausea and vomiting, tissue injury and pain, among others. However, clinical trials with globally acting CB1 antagonists in obesity/metabolic syndrome, and other studies with peripherally restricted CB1/2 agonists and inhibitors of the endocannabinoid metabolizing enzyme in pain introduced unexpected complexities, and suggested that better understanding of the pathophysiological role of the ECS is required in order to devise clinically successful treatment strategies, which will be critically reviewed in this brief synopsis. Journal compilation © 2013 FEBS. No claim to original US government works.
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The endocannabinoid system (ECS) is an old and evolutionarily well preserved neurobiologic system controlling some key elements of organ homeostasis. In contrast to its long biologic history, the scientific record of the ECS is very short. Whereas the occurrence of genes for the endocannabinoid receptors has been described in ancient animals reaching at least as far back as the predecessor of tetrapods (amphibians reptiles, birds, and mammals), modern science has only more recently demonstrated that the ECS is involved in the regulation of a wide range of essential central and peripheral processes which include metabolism and feeding behavior, inflammatory- and anti-inflammatory immunologic reactions, neurobehavioral changes during stress and anxiety and the regulation of central functions such as cognition and memory. One of the most important roles of the ECS lies in the regulation and orchestration of the central and immunologic stress response to aversive and threatening life conditions. There are already data that the ECS is affected in humans during highly aversive conditions of parabolic flights and space flights as well as in other extreme living conditions (e.g. Antarctica). The ECS may therefore have an important function for adaption processes in such aversive conditions.
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Cannabinoids (CB) are a group of molecules that act upon cannabinoid receptors(CBR) and are divided in three categories: Phytocannabinoids (natural terpenophenolic compounds derived from the Cannabis plant species), endocannabinoids (endogenous) and synthetic cannabinoids.
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In this study, urinary metabolic profiles of patients with heart failure (HF) and healthy individuals were analyzed by LC-TOF–MS. Both reversed-phase chromatography and hydrophilic interaction chromatography were used to separate the endogenous metabolites in urine. Partial least-squares to latent structure-discriminant analysis was used for discriminating HF patients from healthy persons and the selection of potential biomarkers. The results suggested that the combination of LC–MS and multivariate statistical analysis could be used for HF diagnosis. The MS/MS experiments were carried out to identify the potential biomarkers which are important for the contribution to the discrimination. As a result, 12 potential biomarkers for HF were identified and the related metabolic pathways were studied.
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Background The role of endocannabinoids such as anandamide during atherogenesis remains largely unknown. Fatty acid amide hydrolase (FAAH) represents the key enzyme in anandamide degradation, and its inhibition is associated with subsequent higher levels of anandamide. Here, we tested whether selective inhibition of FAAH influences the progression of atherosclerosis in mice. Methods and Results Selective inhibition of FAAH using URB597 resulted in significantly increased plasma levels of anandamide compared to control, as assessed by mass spectrometry experiments in mice. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat, cholesterol-rich diet to induce atherosclerotic conditions. Simultaneously, mice received either the pharmacological FAAH inhibitor URB597 1mg/kg body weight (n = 28) or vehicle (n = 25) via intraperitoneal injection three times a week. After eight weeks, mice were sacrificed, and experiments were performed. Vascular superoxide generation did not differ between both groups, as measured by L012 assay. To determine whether selective inhibition of FAAH affects atherosclerotic plaque inflammation, immunohistochemical stainings of the aortic root were performed. Atherosclerotic plaque formation, vascular macrophage accumulation, as well as vascular T cell infiltration did not differ between both groups. Interestingly, neutrophil cell accumulation was significantly increased in mice receiving URB597 compared to control. Vascular collagen structures in atherosclerotic plaques were significantly diminished in mice treated with URB597 compared to control, as assessed by picro-sirius-red staining. This was accompanied by an increased aortic expression of matrix metalloproteinase-9, as determined by quantitative RT-PCR and westernblot analysis. Conclusion Inhibition of fatty acid amide hydrolase does not influence plaque size but increases plaque vulnerability in mice.
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The endocannabinoid system consists of cannabinoid receptors (which mediate the actions of cannabis), their endogenous ligands (endocannabinoids), and the enzymes and proteins associated with their regulation. In brain, the endocannabinoid system functions to modulate the release of other neurotransmitters via the subtype 1 (CB1) receptor. Abnormalities of CB1 receptor expression or endocannabinoid transmission have been associated with several neuropsychiatric diseases. Subtype 2 (CB2) receptors are found primarily on immune and neuroimmune cells and are overexpressed in states of inflammation and neuroinflammation. Both receptors are of particular interest for biomarker development and therapeutic targets. Growing evidence supports the regulation of endocannabinoids as involved in neuropsychiatric and neuroinflammatory diseases. However, the function of endocannabinoid system components in vivo remains difficult to assess. Therefore, the use of functional imaging techniques, such as positron emission tomography (PET), may be particularly useful in the assessment and quantification of the endocannabinoid system. This chapter will cover the current understanding of functional imaging that directly targets the endocannabinoid system.
Hedgehog is a ligand-activated signaling pathway that regulates Gli-mediated transcription. Although most noted for its role as an embryonic morphogen, hyperactive hedgehog also causes human skin and brain malignancies. The hedgehog-related gene anomalies found in these tumors are rarely found in prostate cancer. Yet surveys of human prostate tumors show concordance of high expression of hedgehog ligands and Gli2 that correlate with the potential for metastasis and therapy-resistant behavior. Likewise, prostate cancer cell lines express hedgehog target genes, and their growth and survival is affected by hedgehog/Gli inhibitors. To date, the preponderance of data supports the idea that prostate tumors benefit from a paracrine hedgehog microenvironment similar to the developing prostate. Uncertainty remains as to whether hedgehog’s influence in prostate cancer also includes aspects of tumor cell autocrine-like signaling. The recent findings that Gli proteins interact with the androgen receptor and affect it...
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Isolation of cannabinoids from Cannabis and chemical production of synthetic cannabinoids resulted in understanding of their mechanism of action. Presently, renewed interest in therapeutic potential of cannabinoids is observed. There are numerous studies in the range of chemistry, pharmacology, and molecular biology that investigate the possibilities of their therapeutic application. This review presents results of research on cannabinoids with an emphasis on THC and its effect on a progression of selected diseases. The paper discusses previous reports and outlines future directions.
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The incidence of atherosclerosis is increasing rapidly all over the world. Inflammatory processes have outstanding role in coronary artery disease (CAD) etiology and other atherosclerosis manifestations. Recently attentions have been increased about gut microbiota in many fields of medicine especially in inflammatory diseases like atherosclerosis. Ineffectiveness in gut barrier functions and subsequent metabolic endotoxemia (caused by rise in plasma lipopolysaccharide levels) is associated with low-grade chronic inflammation i.e. a recognized feature of atherosclerosis. Furthermore, the role of trimethylamine-N-oxide (TMAO), a gut bacterial metabolite has been suggested in atherosclerosis development. On the other hand, the effectiveness of gut microbiota modulation that results in TMAO reduction has been investigated. Moreover, considerable evidence supports a role for the endocannabinoid system (ECS) in atherosclerosis pathology which affects gut microbiota, but their effects on atherosclerosis are controversial. Therefore, we presented some evidence about the relationship between gut microbiota and ECS in atherosclerosis. We also presented evidences that gut microbiota modulation by pre/probiotics can have significant influence on the ECS.
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Background: Endocannabinoids (ECs) are rapidly acting immune-modulatory lipid-signaling molecules that are important for adaptation to stressful and aversive situations.They are known to interact with glucocorticoids and other stress-responsive systems. Maladaptation to acute or chronic stress represents a major risk factor for the development of psychiatric disorders. In the present study, we administered stress doses of hydrocortisone ina prospective, randomized, placebo-controlled double blind study in patients undergoing cardiac surgery (CS) to examine the relationship between the use of glucocorticoids, plasma EC levels, and the occurrence of early postoperative cognitive dysfunction (delirium) and of later development of depression. Methods: We determined plasma levels of the ECs anandamide and 2-arachidonoylglycerol (2-AG) in CS patients of the hydrocortisone (n=56) and the placebo group(n=55) preoperatively, at postoperative day (POD) 1, at intensive care unit discharge, and at 6 months after CS(n=68). Postoperative delirium was diagnosed according to Diagnostic and Statistical Manual of the American Psychiatric Association IVth Edition (DSM-IV) criteria, and depression was determined by validated questionnaires and a standardized psychological interview (Structured Clinical Interview for DSM-IV). Results: Stress doses of hydrocortisone did not affect plasma EC levels and the occurrence of delirium or depression. However, patients who developed deliriumon POD 1 had significantly lower preoperative 2-AG levels of the neuroprotective EC 2-AG (median values, 3.8 vs. 11.3ng/ml; p=0.03). Preoperative 2-AG concentrations were predictive of postoperative delirium (sensitivity=0.70;specificity=0.69; cutoff value=4.9 ng/ml; receiver operating characteristic curve area=0.70; 95 o/o confidence interval=0.54-0.85). Patients with depression at 6 months after CS (n=16) had significantly lower anandamide and 2-AG levels during the perioperative period. Conclusions: A low perioperative EC response may indicate an increased risk for early cognitive dysfunction and long-term depression in patients after CS. Glucocorticoids do not seem to influence this relationship.
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The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer’s disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.
Thesis
CB2 Rezeptor Aktivierung zeigte in einer Reihe inflammatorischer Krankheitsmodelle eine anti-inflammatorische Wirksamkeit. Viele Daten deuten auch bei der Atherosklerose darauf hin, dass der Cannabinoid Rezeptor 2 (CB2) eine protektive Rolle bei der Inflammation und Atherosklerose spielt. Allerdings gibt es keine direkten Beweise, um diese Hypothese zu belegen. Aus diesem Grund wurde diese Studie konzipiert, um den Einfluß des CB2 Rezeptors auf die Atherogenese in Mäusen gezielt zu untersuchen. Low-density-lipoprotein receptor defiziente (LDLR-/-) Tiere erhielten während einer 16 wöchigen Fütterungsstudie mit cholesterinreicher Diät (HCD) dreimal wöchentlich eine intraperitoneale Injektion von JWH-133, einem selektiven CB2 Rezeptor Agonist, oder Tocrisolve, der Trägerlösung. Entgegen der Hypothese war die Größe der intimalen Läsionen in beiden Gruppen in der histologische Auswertung der Aortenwurzeln und –bögen ähnlich. Die Plaquekomposition wurde nicht verändert, die Anteile von Lipiden, Makrophagen, glatten Muskelzellen, T-Zellen und Kollagen waren in beiden Gruppen vergleichbar. Diese Daten deuten darauf hin, dass die CB2 Rezeptor Aktivierung die Atherogenese in-vivo nicht beeinflusst. Desweiteren entwickelten CB2-/-/LDLR-/- Tiere ähnlich große atherosklerotische Plaques wie die CB2+/+/LDLR-/- Kontrolltiere, während die CB2 defizienten Tiere einen höheren Makrophagen- und Lipidgehalt in der Plaquekomposition zeigten. Die Anteile an glatten Muskelzellen und Kollagenfasern war allerdings in beiden Gruppen gleich, was darauf hin deutet, dass die Plaquestabilität nicht beeinflußt ist. JWH-133 Behandlung zeigte anti-inflammatorische Wirkungen und verringerte in einer Thioglykolat-induzierten Peritonitis nach 72 Stunden die Zahl der eingewanderten Leukozyten. Auch die TNFα-induzierte Rekruitierung von inflammatorischen Ly6C/Gr-1high Monozyten in den Blutpool konnte durch JWH-133 signifikant reduziert werden. Allerdings bewirkte weder die pharmakologische CB2 Rezeptor Aktivierung noch die genetische Deletion eine signifikante Veränderung der inflammatorischen Zytokinexpression in-vivo, der Zelladhäsion in der Flusskammer in-vitro oder der ICAM-1 Expression und MCP-1 Ausschüttung von murinen Endothelzellen in-vitro. Diese Ergebnisse zeigen, dass weder die Aktivierung noch die Deletion des CB2 Rezeptors die Atherogenese in Mäusen relevant beeinflußt. Wie in anderen Studien gezeigt, spielen CB2 Rezeptor Signalwege in verschiedenen inflammatorischen Prozessen eine wichtige Rolle. Im Rahmen der Atherosklerose erscheint dieser Rezeptor aber nicht als ein geeignetes therapeutisches Ziel, um die Größe der atherosklerotischen Plaques zu reduzieren.
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The endocannabinoid system (ECS) is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB ). In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells) and intracellular compartments (e.g., mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons). Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.
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The endocannabinoïd system (ECS) is involved in many biological functions such as regulation of energy metabolism. Recently, several studies have shown an association between obesity and ECS overactivity. In addition, specific CB1R antagonists such as Rimonabant (SR141716) improved metabolic parameters in obese patients essentially through inactivation of central CB1R. However, peripheral CB1R inactivation could also contribute to the improvement of these parameters and it is this notion that we have studied. To this purpose, we tested the effects of SR141716 on obese mice in order to establish relationships between the ECS activity and lipid metabolism by looking more specifically to its regulation in two key tissues, the liver and the adipose tissue (AT). Obese mice previously fed with a high sucrose high fat diet were treated six weeks by SR141716 and this treatment induced weight loss associated with a normalization of plasmatic parameters and a reduction of hepatic steatosis. The major hypothesis of this study is that steatosis reversion was associated with a beneficial effect of treatment on visceral AT metabolism and that SR141716 would have direct effects on peripheral tissues. Therefore, these effects of CB1R antagonism on peripheral lipid metabolism have been studied in vitro. In this way, we first developed a model of liver explants in culture treated with SR141716. In this model, CB1R antagonism in the liver was associated with a decrease in CB1 gene expression and in certain conditions with an increased in -oxidative capacity. Finally, in order to study the impact of the ECS on adipocyte metabolism, we developed a model of cultured AT explants distinguishing visceral and subcutaneous AT. Preliminary results suggested that CB1R antagonism limits lipolysis in visceral AT. In conclusion, this work showed that peripheral CB1R are a very promising therapeutic target for treating obesity and related disorders.
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Correction to: The EMBO Journal (2005) 24, 3026–3037. doi:10.1038/sj.emboj.7600784
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The endocannabinoid 2-arachidonoylglycerol (2-Δ4Ach-Gro) activates human platelets in platelet-rich plasma at physiological concentrations. The activation was inhibited by selective antagonists of CB1 and CB2 cannabinoid receptors, but not by acetylsalicylic acid. Human platelets can metabolize 2-Δ4Ach-Gro by internalization through a high affinity transporter (Km = 300 ± 30 nm, Vmax = 10 ± 1 pmol·min−1·mg protein−1), followed by hydrolysis by a fatty acid amide hydrolase (Km = 8 ± 1 µm, Vmax = 400 ± 50 pmol·min−1·mg protein−1). The anandamide transport inhibitor AM404, and anandamide itself, were ineffective on 2-Δ4Ach-Gro uptake by platelets, whereas anandamide competitively inhibited 2-Δ4Ach-Gro hydrolysis (inhibition constant = 10 ± 1 µm). Platelet activation by 2-Δ4Ach-Gro was paralleled by an increase of intracellular calcium and inositol-1,4,5-trisphosphate, and by a decrease of cyclic AMP. Moreover, treatment of preloaded platelet-rich plasma with 2-Δ4Ach-Gro induced an approximately threefold increase in [3H]2-Δ4Ach-Gro release, according to a CB receptor-dependent mechanism. On the other hand, ADP and collagen counteracted the activation of platelets by 2-Δ4Ach-Gro, whereas 5-hydroxytryptamine (serotonin) enhanced and extended its effects. Remarkably, ADP and collagen also reduced [3H]2-Δ4Ach-Gro release from 2-Δ4Ach-Gro-activated platelets, whereas 5-hydroxytryptamine further increased it. These findings suggest a so far unnoticed interplay between the peripheral endocannabinoid system and physiological platelet agonists.
Article
The stimulus-induced biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in intact mouse J774 macrophages and the inactivation of 2-AG by the same cells or by rat circulating macrophages was studied. By using gas chromatography-mass spectrometry, we found that ionomycin (5 µm) and lipopolysaccharide (LPS, 200 µg·mL−1) cause a 24-fold and 2.5-fold stimulation of 2-AG levels in J774 cells, respectively, thus providing unprecedented evidence that this cannabimimetic metabolite can be synthesized by macrophages. In J774 cells, LPS also induced a 7.8-fold increase of the levels of the other endocannabinoid, anandamide, and, in rat circulating macrophages, an almost twofold increase of 2-AG levels. Extracellular [3H]2-AG was cleared from the medium of intact J774 macrophages (t1/2 = 19–28 min) and esterified to phospholipids, diacylglycerols and triglycerides or hydrolyzed to [3H]arachidonic acid and glycerol. These catabolic processes were attenuated differentially by various enzyme inhibitors. Rat circulating macrophages were shown to contain enzymatic activities for the hydrolysis of 2-AG, including: (a) fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide breakdown and previously shown to catalyse also 2-AG hydrolysis, and (b) a 2-AG hydrolase activity different from FAAH and down-regulated by LPS. High levels of FAAH mRNA were found in circulating macrophages but not platelets, which, however, contain a 2-AG hydrolase. Both platelets and macrophages were shown to express the mRNA for the CB1 cannabinoid receptor. A macrophage 2-AG hydrolase with apparent Km = 110 µm and Vmax = 7.9 nmol·min−1·(mg protein)−1 was partially characterized in J774 cells and found to exhibit an optimal pH of 6–7 and little or no sensitivity to typical FAAH inhibitors. These findings demonstrate for the first time that macrophages participate in the homeostasis of the hypotensive and immunomodulatory endocannabinoid 2-AG through metabolic mechanisms that are subject to regulation.
Article
Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.
Article
Cannabinoids, including the endogenous ligand anandamide (arachidonyl ethanolamide), elicit pronounced hypotension in rats via activation of peripherally located CB1 cannabinoid receptors, which have been also implicated in endotoxin (lipopolysaccharide [LPS])-induced hypotension. The present study was designed to test the role of vascular CB1 receptors in cannabinoid- and endotoxin-induced mesenteric vasodilation. In the isolated, buffer-perfused rat mesenteric arterial bed precontracted with phenylephrine, anandamide induced long-lasting (up to 60 minutes) dose-dependent vasodilation (ED50: 79+/-3 nmol; maximal relaxation: 77+/-2%), inhibited by 0.5 to 5.0 micromol/L of the selective CB1 receptor antagonist SR141716A. Low doses of the calcium ionophore ionomycin also caused mesenteric vasodilation inhibited by SR141716A. The metabolically stable analogue R-methanandamide elicited mesenteric vasodilation (ED50: 286+/-29 nmol), whereas the potent synthetic CB1 receptor agonists WIN 55212-2 and HU-210 caused no change in vascular tone or only a minor dilator effect not affected by SR141716A, respectively. The endogenous ligand 2-arachidonyl glycerol caused no change in vascular tone, whereas Delta9-tetrahydrocannabinol and arachidonic acid caused mesenteric vasoconstriction. After endothelial denudation, the dilator response to anandamide was slightly reduced and was no longer inhibited by SR141716A. In preparations from LPS-pretreated rats, SR141716A alone caused a significant and prolonged increase in perfusion pressure, whereas it had no such effect in control preparations perfused in vitro with or without LPS or after endothelial denudation in preparations from rats pretreated with LPS. We conclude that anandamide-induced mesenteric vasodilation is mediated by an endothelially located SR141716A-sensitive "anandamide receptor" distinct from CB1 cannabinoid receptors and that activation of such receptors by an endocannabinoid, possibly anandamide, contributes to LPS-induced mesenteric vasodilation in vivo.
Article
Anandamide (arachidonoylethanolamide, AnNH) is shown to activate human platelets, a process which was not inhibited by acetylsalicylic acid (aspirin). Unlike AnNH, hydroperoxides generated thereof by lipoxygenase activity, and the congener (13-hydroxy)linoleoylethanolamide, were unable to activate platelets, though they counteracted AnNH-mediated stimulation. On the other hand, palmitoylethanolamide neither activated human platelets nor blocked the AnNH effects. AnNH inactivation by human platelets was afforded by a high-affinity transporter, which was activated by nitric oxide-donors up to 225% of the control. The internalized AnNH could thus be hydrolyzed by a fatty acid amide hydrolase (FAAH), characterized here for the first time.
Article
The mechanisms involved in body weight regulation in humans include genetic, physiological, and behavioral factors. Stability of body weight and body composition requires that energy intake matches energy expenditure and that nutrient balance is achieved. Human obesity is usually associated with high rates of energy expenditure. In adult individuals, protein and carbohydrate stores vary relatively little, whereas adipose tissue mass may change markedly. A feedback regulatory loop with three distinct steps has been recently identified in rodents: 1) a sensor that monitors the size of adipose tissue mass is represented by the amount of leptin synthesized by adipose cells (a protein encoded by the ob gene) which determines the plasma leptin levels; 2) hypothalamic centers, with specific leptin receptors, which receive and integrate the intensity of the signal; and 3) effector systems that influence the two determinants of energy balance, i.e., energy intake and energy expenditure. With the exception of a few very rare cases, the majority of obese human subjects have high plasma leptin levels that are related to the size of their adipose tissue mass. However, the expected regulatory responses (reduction in food intake and increase in energy expenditure) are not observed in obese individuals. Thus obese humans are resistant to the effect of endogenous leptin, despite unaltered hypothalamic leptin receptors. Whether defects in the leptin signaling cascade play a role in the development of human obesity is a field of great actual interest that needs further research. Present evidences suggest that genetic and environmental factors influence eating behavior of people prone to obesity and that diets that are high in fat or energy dense undermine body weight regulation by promoting an overconsumption of energy relative to need.
Article
Anandamide (ANA), a cannabinoid receptor ligand, stimulated platelet aggregation at concentrations similar to those of arachidonic acid (AA). The aggregating effect of ANA was inhibited by aspirin but not by SR-141716, a cannabinoid receptor antagonist. In addition, HU-210, a cannabinoid receptor agonist, failed to induce platelet activation. Radiolabelling experiments showed that exogenous ANA was cleaved by platelets into AA through a phenylmethylsulfonyl fluoride (PMSF)-sensitive pathway. In agreement, PMSF was shown to abolish the aggregating effect of ANA. In conclusion, ANA is able to induce platelet activation via its cleavage by a PMSF-sensitive amidase activity, leading to the release of AA which in turn activates platelets.
Article
Atherosclerosis, a disease of the large arteries, is the primary cause of heart disease and stroke. In westernized societies, it is the underlying cause of about 50% of all deaths. Epidemiological studies have revealed several important environmental and genetic risk factors associated with atherosclerosis. Progress in defining the cellular and molecular interactions involved, however, has been hindered by the disease's aetiological complexity. Over the past decade, the availability of new investigative tools, including genetically modified mouse models of disease, has resulted in a clearer understanding of the molecular mechanisms that connect altered cholesterol metabolism and other risk factors to the development of atherosclerotic plaque. It is now clear that atherosclerosis is not simply an inevitable degenerative consequence of ageing, but rather a chronic inflammatory condition that can be converted into an acute clinical event by plaque rupture and thrombosis.
Article
After the discovery, in the early 1990s, of specific G-protein-coupled receptors for marijuana's psychoactive principle Δ9-tetrahydrocannabinol, the cannabinoid receptors, and of their endogenous agonists, the endocannabinoids, a decade of investigations has greatly enlarged our understanding of this altogether new signalling system. Yet, while the finding of the endocannabinoids resulted in a new effort to reveal the mechanisms regulating their levels in the brain and peripheral organs under physiological and pathological conditions, more endogenous substances with a similar action, and more molecular targets for the previously discovered endogenous ligands, anandamide and 2-arachidonoylglycerol, or for some of their metabolites, were being proposed. As the scenario becomes subsequently more complicated, and the experimental tasks to be accomplished correspondingly more numerous, we briefly review in this article the latest ‘additions’ to the endocannabinoid system together with earlier breakthroughs that have contributed to our present knowledge of the biochemistry and pharmacology of the endocannabinoids. British Journal of Pharmacology (2004) 141, 765–774. doi:10.1038/sj.bjp.0705666
Article
Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. As a hormone, leptin regulates food intake and basal metabolism, and is sexually dimorphic - that is, its serum concentration is higher in females than in males with a similar body fat mass. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 and tumour-necrosis factor. Similar to other pro-inflammatory cytokines, leptin promotes T helper 1 (TH1)-cell differentiation and can modulate the onset and progression of autoimmune responses in several animal models of disease. Here, we review the advances and controversy for a role of leptin in the pathophysiology of immune responses.
Article
The cardiovascular actions of cannbinoids are complex. In general they cause vasorelaxation in isolated blood vessels, while in anaesthetised animals they cause multiphasic responses which involve an early bradycardia and long-lasting hypotension. However, in conscious animals, the picture is one of bradycardia followed by pressor responses. Clearly, the responses to cannabinoids are dependent on the experimental conditions and synthetic cannabinoids and endocannabinoids exhibit different pharmacologies. In terms of mechanisms involved in the vascular responses to cannabinoids, the following have been implicated: the involvement of ‘classical’ cannabinoid receptors, the involvement of a novel endothelial cannabinoid receptor, the release of nitric oxide, the release of endothelium-derived hyperpolarising factor (EDHF), the activation of vanilloid receptors, metabolism of endocannabinoids to vasoactive molecules, and both peripheral inhibition and central excitation of the sympathetic nervous system. British Journal of Pharmacology (2004) 142, 20–26. doi:10.1038/sj.bjp.0705725
Article
Obesity is a major underlying risk factor for ASCVD. It is associated with multiple ASCVD risk factors, and it also is a risk factor for type 2 diabetes. Diabetes itself is a cardiovascular risk factor. Despite the strong association between obesity and ASCVD, the mechanisms underlying this relationship are not well understood. Our understanding of the connection between obesity and vascular disease is complicated by a plethora of possibilities. Obesity acts on so many metabolic pathways, producing so many potential risk factors, that it is virtually impossible to differentiate between the more important and less important. The possibilities for confounding variables are enormous. This complexity provides a great challenge for basic and clinical research. It also raises the possibility for new targets of therapy for the metabolic syndrome. With this said, the fundamental challenge is how to intervene at the public health level to reduce the high prevalence of obesity in the general population. This approach offers the greatest possibility for reducing the cardiovascular risk that accompanies obesity.
Article
Of novel risk factors for cardiovascular disease currently under investigation, high-sensitivity C-reactive protein (hsCRP) is the most promising. To date, more than 20 prospective epidemiologic studies have demonstrated that hsCRP independently predicts vascular risk, 6 cohort studies have confirmed that hsCRP evaluation adds prognostic information beyond that available from the Framingham Risk Score, and 8 cohort studies have demonstrated additive prognostic value at all levels of metabolic syndrome or in the prediction of type 2 diabetes. In contrast to several other biomarkers that also reflect biological aspects of inflammation, hypofibrinolysis, and insulin resistance, hsCRP measurement is inexpensive, standardized, widely available, and has a decade-to-decade variation similar to that of cholesterol. Given the consistency of prognostic data for hsCRP and the practicality of its use in outpatient clinical settings, we believe the time has come for a careful consideration of adding hsCRP as a clinical criterion for metabolic syndrome and for the creation of an hsCRP-modified coronary risk score useful for global risk prediction in both men and women. Toward this end, we believe experts in the fields of epidemiology, prevention, vascular biology, and clinical cardiology should be convened to begin discussing the merits of this proposal.
Article
Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension. In spontaneously hypertensive rats (SHR), cannabinoid-1 receptor (CB1) antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility, and vascular resistance to levels in normotensive rats, and these effects are prevented by CB1 antagonists. Similar changes are observed in 2 additional models of hypertension, whereas in normotensive control rats, the same parameters remain unaffected by any of these treatments. CB1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB1 is increased in heart and aortic endothelium of SHR compared with Wistar-Kyoto rats. We conclude that endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB1-mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension.
Article
It becomes increasingly evident that blood platelets do not only exert important functions in hemostasis and thrombus formation but are also involved in atherosclerotic vascular disease. A major portion of the underlying mechanisms is related to an intricate functional interaction of platelets with chemokines, which have also been implicated in atherogenesis and neointima formation: (1) Platelets can induce the secretion of chemokines in different cells of the vascular wall; (2) In combination with primary agonists, certain chemokines can potentiate platelet aggregation and adhesion; (3) Activated platelets can release and deposit chemokines and precursors on vascular cell surfaces, which trigger atherogenic recruitment of vascular cells or modulate crucial processes such as angiogenesis and lipoprotein metabolism; (4) Surface-adherent platelets can bind and present vascular cell-derived chemokines to trigger arrest of circulating mononuclear cells. The close linkage between platelets and chemokines as culprits in the pathogenesis of vascular diseases may provide a valuable target for selective interventions.
Article
Atherosclerosis is a chronic inflammatory disease, and is the primary cause of heart disease and stroke in Western countries. Derivatives of cannabinoids such as delta-9-tetrahydrocannabinol (THC) modulate immune functions and therefore have potential for the treatment of inflammatory diseases. We investigated the effects of THC in a murine model of established atherosclerosis. Oral administration of THC (1 mg kg(-1) per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, we detected the CB2 receptor (the main cannabinoid receptor expressed on immune cells) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-gamma secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist. Our data demonstrate that oral treatment with a low dose of THC inhibits atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis.