title: The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques.
abstract: OBJECTIVE
  The activation of cannabinoid receptor type 2 (CB(2))-mediated pathways might represent a promising anti-atherosclerotic treatment. Here, we investigated the expression of the endocannabinoid system in human carotid plaques and the impact of CB(2) pharmacological activation on markers of plaque vulnerability in vivo and in vitro.
  
  
  RESULTS
  The study was conducted using all available residual human carotid tissues (upstream and downstream the blood flow) from our cohort of patients symptomatic (n = 13) or asymptomatic (n = 27) for ischaemic stroke. Intraplaque levels of 2-arachidonoylglycerol, anandamide N-arachidonoylethanolamine, N-palmitoylethanolamine, N-oleoylethanolamine, and their degrading enzymes (fatty acid amide hydrolase and monoacylglycerol lipase) were not different in human plaque portions. In the majority of human samples, CB(1) (both mRNA and protein levels) was undetectable. In downstream symptomatic plaques, CB(2) protein expression was reduced when compared with asymptomatic patients. In these portions, CB(2) levels were inversely correlated (r = -0.4008, P = 0.0170) with matrix metalloprotease (MMP)-9 content and positively (r = 0.3997, P = 0.0174) with collagen. In mouse plaques, CB(2) co-localized with neutrophils and MMP-9. Treatment with the selective CB(2) agonist JWH-133 was associated with the reduction in MMP-9 content in aortic root and carotid plaques. In vitro, pre-incubation with JWH-133 reduced tumour necrosis factor (TNF)-α-mediated release of MMP-9. This effect was associated with the reduction in TNF-α-induced ERK1/2 phosphorylation in human neutrophils.
  
  
  CONCLUSIONS
  Cannabinoid receptor type 2 receptor is down-regulated in unstable human carotid plaques. Since CB(2) activation prevents neutrophil release of MMP-9 in vivo and in vitro, this treatment strategy might selectively reduce carotid vulnerability in humans.
authors: Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, Geneva University Hospitals, avenue de la Roseraie 64, 1211 Geneva 4, Switzerland. fabrizio.montecucco@unige.ch
authors: Fabrizio
authors: F
authors: Montecucco
authors: Vincenzo
authors: V
authors: Di Marzo
authors: Rafaela F
authors: RF
authors: da Silva
authors: Nicolas
authors: N
authors: Vuilleumier
authors: Luciano
authors: L
authors: Capettini
authors: Sébastien
authors: S
authors: Lenglet
authors: Sabrina
authors: S
authors: Pagano
authors: Fabiana
authors: F
authors: Piscitelli
authors: Silvia
authors: S
authors: Quintao
authors: Maria
authors: M
authors: Bertolotto
authors: Graziano
authors: G
authors: Pelli
authors: Katia
authors: K
authors: Galan
authors: Lucie
authors: L
authors: Pilet
authors: Kristina
authors: K
authors: Kuzmanovic
authors: Fabienne
authors: F
authors: Burger
authors: Bianca
authors: B
authors: Pane
authors: Giovanni
authors: G
authors: Spinella
authors: Vincent
authors: V
authors: Braunersreuther
authors: Angèle
authors: A
authors: Gayet-Ageron
authors: Aldo
authors: A
authors: Pende
authors: Giorgio Luciano
authors: GL
authors: Viviani
authors: Domenico
authors: D
authors: Palombo
authors: Franco
authors: F
authors: Dallegri
authors: Pascale
authors: P
authors: Roux-Lombard
authors: Robson A S
authors: RA
authors: Santos
authors: Nikos
authors: N
authors: Stergiopulos
authors: Sabine
authors: S
authors: Steffens
authors: François
authors: F
authors: Mach
mesh_terms: D000368:Aged; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology; D002343:Carotid Artery, Internal / Q000378:metabolism*; D016893:Carotid Stenosis / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002186:Cannabinoids; D005419:Flavonoids; D007211:Indoles; D047428:Protein Kinase Inhibitors; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C094023:iodopravadoline