title: CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion.
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.
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Department of Internal Medicine, University Hospital, Geneva, Switzerland.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lenglet
authors.forename: Vincent
authors.initials: V
authors.lastname: Braunersreuther
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Maria
authors.initials: M
authors.lastname: Bertolotto
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002630:Chemotactic Factors / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000201:enzymology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D039481:CD11b Antigen; D002186:Cannabinoids; D002630:Chemotactic Factors; D017382:Reactive Oxygen Species; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC