The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques.

Abstract

AIMS:

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.

METHODS AND 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.

CONCLUSION:

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: Fabrizio Montecucco, Vincenzo Di Marzo, Rafaela F da Silva, Nicolas Vuilleumier, Luciano Capettini, Sébastien Lenglet, Sabrina Pagano, Fabiana Piscitelli, Silvia Quintao, Maria Bertolotto, Graziano Pelli, Katia Galan, Lucie Pilet, Kristina Kuzmanovic, Fabienne Burger, Bianca Pane, Giovanni Spinella, Vincent Braunersreuther, Angèle Gayet-Ageron, Aldo Pende, Giorgio Luciano Viviani, Domenico Palombo, Franco Dallegri, Pascale Roux-Lombard, Robson A S Santos, Nikos Stergiopulos, Sabine Steffens, François Mach
• Journal: European heart journal (Eur Heart J) Vol. 33 Issue 7 Pg. 846-56 (Apr 2012) ISSN: 1522-9645 [Electronic] England
• PMID: 22112961 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cannabinoids
• Flavonoids
• Indoles
• Protein Kinase Inhibitors
• Receptor, Cannabinoid, CB2
• Tumor Necrosis Factor-alpha
• Matrix Metalloproteinase 9
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
• 1,1-dimethylbutyl-1-deoxy-Delta(9)-THC
• iodopravadoline

Topics

• Aged
• Animals
• Aorta, Thoracic (metabolism)
• Cannabinoids (pharmacology)
• Carotid Artery, Internal (metabolism)
• Carotid Stenosis (metabolism)
• Case-Control Studies
• Female
• Flavonoids (pharmacology)
• Humans
• Indoles (pharmacology)
• MAP Kinase Signaling System (physiology)
• Male
• Matrix Metalloproteinase 9 (metabolism, physiology)
• Mice
• Mice, Inbred C57BL
• Neutrophils (metabolism)
• Phosphorylation (physiology)
• Plaque, Atherosclerotic (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Receptor, Cannabinoid, CB2 (antagonists & inhibitors, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)