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CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion

Bertolotto, Maria
Published in Journal of Molecular and Cellular Cardiology. 2009, vol. 46, no. 5, p. 612-620
Abstract 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-alpha, and ICAM-1 expression levels were found. Furthermore, JWH-133 inhibited the TNF-alpha 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.
Keywords AnimalsAntigens, CD11b/metabolismCannabinoids/administration & dosage/pharmacologyCell Movement/drug effectsChemotactic Factors/metabolismDisease Models, AnimalHumansIntercellular Adhesion Molecule-1/metabolismIntracellular Space/drug effects/metabolismMiceMyocardial Infarction/complications/metabolism/pathologyMyocardial Reperfusion Injury/complications/enzymology/*prevention & controlMyocardium/enzymology/*metabolism/pathologyNeutrophils/cytology/drug effectsOxidative Stress/drug effectsReactive Oxygen Species/metabolismReceptor, Cannabinoid, CB2/agonists/*metabolismSignal Transduction/drug effectsTumor Necrosis Factor-alpha/pharmacology
PMID: 19162037
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Research groups Biologie du myocarde (22)
L'athérosclérose et ses complications cliniques (591)
Le rôle du système endocannabinoïde dans l'athérosclérose (882)
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MONTECUCCO, Fabrizio et al. CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. In: Journal of Molecular and Cellular Cardiology, 2009, vol. 46, n° 5, p. 612-620. doi: 10.1016/j.yjmcc.2008.12.014 https://archive-ouverte.unige.ch/unige:19976

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Deposited on : 2012-04-23

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