Cannabinoid receptor type 2 activation in atherosclerosis and acute cardiovascular diseases (original) (raw)
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Cannabinoid Receptor 2 Signaling Does Not Modulate Atherogenesis in Mice
PLOS One, 2011
Background: Strong evidence supports a protective role of the cannabinoid receptor 2 (CB 2 ) in inflammation and atherosclerosis. However, direct proof of its involvement in lesion formation is lacking. Therefore, the present study aimed to characterize the role of the CB 2 receptor in Murine atherogenesis.
Cannabinoid receptors in acute and chronic complications of atherosclerosis
British Journal of Pharmacology, 2008
Atherosclerosis is a chronic inflammatory disease that is the primary cause of myocardial infarction and stroke, which occur after sudden thrombotic occlusion of an artery. A growing body of evidence suggests that cannabinoid signalling plays a fundamental role in atherosclerosis development and its clinical manifestations. Thus, CB 2 receptors are protective in myocardial ischaemia/reperfusion and implicated in the modulation of chemotaxis, which is crucial for the recruitment of leukocytes during inflammation. Delta-9-Tetrahydrocannabinol (THC)-mediated activation has been shown to inhibit atherosclerotic plaque progression in a CB 2 dependent manner. Although CB 1 and CB 2 expression has been reported on platelets, their involvement in thrombus formation is still controversial. While several reports suggest that CB 1 receptors may have a relevant role in neuroprotection after ischaemic stroke, recent studies show the protective effects in various forms of neuroprotection are not related to CB 1 stimulation, and a protective role of CB 1 blockade has also been reported. In addition, vascular and myocardial CB 1 receptors contribute to the modulation of blood pressure and heart rate. It is tempting to suggest that pharmacological modulation of the endocannabinoid system is a potential novel therapeutic strategy in the treatment of atherosclerosis. For these purposes, it is important to better understand the complex mechanisms of endocannabinoid signalling and potential consequences of its pharmacological modulation, as it may have both pro-and anti-atherosclerotic effects.
British Journal of Pharmacology, 2008
Background and purpose: Vascular smooth muscle proliferation and migration triggered by inflammatory stimuli are involved in the development and progression of atherosclerosis and restenosis. Cannabinoids may modulate cell proliferation in various cell types through cannabinoid 2 (CB 2 ) receptors. Here, we investigated the effects of CB 2 receptor agonists on TNF-a-induced proliferation, migration and signal transduction in human coronary artery smooth muscle cells (HCASMCs). Experimental approach: HCASMCs were stimulated with TNF-a. Smooth muscle proliferation was determined by the extent of BrdU incorporation and the migration was assayed by modified Boyden chamber. CB 2 and/or CB 1 receptor expressions were determined by immunofluorescence staining, western blotting, RT-PCR, real-time PCR and flow cytometry. Key results: Low levels of CB 2 and CB 1 receptors were detectable in HCASMCs compared to the high levels of CB 2 receptors expressed in THP-1 monocytes. TNF-a triggered up to B80% increase (depending on the method used) in CB 2 receptor mRNA and/or protein expression in HCASMCs, and induced Ras, p38 MAPK, ERK 1/2, SAPK/JNK and Akt activation, while increasing proliferation and migration. The CB 2 agonists, JWH-133 and HU-308, dose-dependently attenuated these effects of TNF-a. Conclusions and implications: Since the above-mentioned TNF-a-induced phenotypic changes are critical in the initiation and progression of atherosclerosis and restenosis, our findings suggest that CB 2 agonists may offer a novel approach in the treatment of these pathologies by decreasing vascular smooth muscle proliferation and migration.
British Journal of Pharmacology, 2003
1 To study the long-term effects of altered cannabinoid receptor activity on myocardial and vascular function, Wistar rats were treated with the selective CB 1 antagonist AM-251 (0.5 mg kg À1 d À1 ), the potent synthetic cannabinoid HU-210 (50 mg kg À1 d À1 ) or vehicle for 12 weeks after coronary artery ligation or sham operation. 2 AM-251 further reduced the pressure-generating capacity, shifted the pressure volume curve to the right (Po0.05) and increased the left-ventricular operating volume (AM-251: 930740 ml vs control: 820740 ml vs HU-210: 790750 ml; Po0.05) in rats with large myocardial infarction (MI). 3 Left-ventricular CB 1 immunoactivity in rats 12 weeks after large MI was unaltered as compared with noninfarcted hearts. 4 Cannabinoid receptor activation through HU-210, a cannabinoid that alters cardiovascular parameters via CB 1 receptors, increased the left-ventricular end-diastolic pressure (LVEDP, Po0.05). However, it prevented the drop in left-ventricular systolic pressure (HU-210: 14275 mm Hg; Po0.05 vs control: 12473 mm Hg; and Po0.001 vs AM-251: 11473 mm Hg) and prevented endothelial dysfunction (ED) in aortic rings of rats with large MI (Po0.05). 5 Compared with AM-251, HU-210 prevented the decline in the maximal rate of rise of leftventricular pressure and the maximum pressure-generating ability (Po0.05). In rats with small MI, HU-210 increased cardiac index (Po0.01) and lowered the total peripheral resistance (Po0.05). 6 The study shows that during the development of congestive heart failure post-large MI, cannabinoid treatment increases LVEDP and prevents hypotension and ED. Presumed CB 1 antagonism promotes remodeling despite unchanged myocardial CB 1 expression. index; dP/dt max , maximal rate of rise of left-ventricular systolic pressure; ED, endothelial dysfunction; HR, heart rate; HU-210, {-}-11-OH-D 9 tetrahydrocannabinol dimethylheptyl; LVEDP, left-ventricular end-diastolic pressure; MAP, mean arterial pressure; MI, myocardial infarction; SVI, stroke volume index; TPRI, total peripheral resistance index
CB2 cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion
Journal of Molecular and Cellular Cardiology, 2009
Preventive treatment with cannabinoid agonists has been reported to reduce the infarct size in a mouse model of myocardial ischemia/reperfusion. Here we investigated the possible cardioprotective effect of selective CB 2 cannabinoid receptor activation during ischemia. We performed left coronary artery ligature in C57Bl/6 mice for 30 min, followed by 24 h of reperfusion. Five minutes before reperfusion, mice received intraperitoneal injection of the CB 2 selective agonist JWH-133 (20 mg/kg) or vehicle. Infarct size was assessed histologically and by cardiac troponin I (cTnI) ELISA. Immunohistochemical analysis of leukocyte infiltration, oxidative stress in situ quantification, real-time RT-PCR analysis of inflammatory mediators as well as western blots for kinase phosphorylation was also performed. In addition, we studied chemotaxis and integrin expression of human neutrophils in vitro. JWH-133 significantly reduced the infarct size (I/area at risk: 19.27% ± 1.91) as compared to vehicle-treated mice (31.77% ± 2.7). This was associated with a reduction of oxidative stress and neutrophil infiltration in the infarcted myocardium, whereas activation of ERK 1/2 and STAT-3 was increased. Preinjection of PI3K inhibitor LY294002, MEK 1/2 inhibitor U0126 and JAK-2 inhibitor AG-490 partially abrogated the JWH-133 mediated infarct size reduction. No changes in cardiac CXCL1, CXCL2, CCL3, TNF-α, and ICAM-1 expression levels were found. Furthermore, JWH-133 inhibited the TNF-α induced chemotaxis and integrin CD18/CD11b (Mac-1) upregulation on human neutrophils. Our data suggest that JWH-133 administration during ischemia reduces the infarct size in a mouse model of myocardial ischemia/reperfusion through a direct cardioprotective activity on cardiomyocytes and neutrophils.
Basic Research in Cardiology, 2014
Ischemic heart disease is associated with inflammation, interstitial fibrosis and ventricular dysfunction prior to the development of heart failure. Endocannabinoids and the cannabinoid receptor CB2 have been claimed to be involved, but their potential role in cardioprotection is not well understood. We therefore explored the role of the cannabinoid receptor CB2 during the initial phase of ischemic cardiomyopathy development prior to the onset of ventricular dysfunction or infarction. Wild type and CB2-deficient mice underwent daily brief, repetitive ischemia and reperfusion (I/R) episodes leading to ischemic cardiomyopathy. The relevance of the endocannabinoid-CB2 receptor axis was underscored by the finding that CB2 was upregulated in ischemic wild type cardiomyocytes and that anandamide level was transiently increased during I/R. CB2-deficient mice showed an increased rate of apoptosis, irreversible loss of cardiomyocytes and persistent left ventricular dysfunction 60 days after the injury, whereas wild type mice presented neither morphological nor functional defects. These defects were due to lack of cardiomyocyte protection mechanisms, as CB2-deficient hearts were in contrast to controls unable to induce switch in myosin heavy chain isoforms, antioxidative enzymes and chemokine CCL2 during repetitive I/R. In addition, a prolonged inflammatory response and adverse myocardial remodeling were found in CB2-deficient hearts because of postponed activation of the M2a macrophage subpopulation. Therefore, the endocannabinoid-CB2 receptor axis plays a key role in cardioprotection during the initial phase of ischemic cardiomyopathy development.