Cannabinoid receptor 2 signaling does not modulate atherogenesis in mice

• Published in: PloS one 2011-04, Vol.6 (4), p.e19405
• Main Authors: Willecke, Florian, Zeschky, Katharina, Ortiz Rodriguez, Alexandra, Colberg, Christian, Auwärter, Volker, Kneisel, Stefan, Hutter, Melanie, Lozhkin, Andrey, Hoppe, Natalie, Wolf, Dennis, von zur Mühlen, Constantin, Moser, Martin, Hilgendorf, Ingo, Bode, Christoph, Zirlik, Andreas
• Format: Article
• Language: English
• Subjects: Animals; Aorta; Apoptosis; Arches; Arteriosclerosis; Atherogenesis; Atherosclerosis; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biology; Cannabinoid CB2 receptors; Cannabinoids - pharmacokinetics; Cannabinoids - pharmacology; Cardiology; Cell activation; Cell adhesion; Cell Survival - drug effects; Cholesterol; Clonal deletion; Collagen; Cytokines; Cytokines - metabolism; Disease; Disease Models, Animal; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Feeding Behavior - drug effects; High cholesterol diet; Inflammation; Inflammation - pathology; Intercellular Adhesion Molecule-1 - metabolism; Ischemia; Lesions; Ligands; Lipids; Lipoprotein (low density) receptors; Low density lipoprotein receptors; Lymphocytes; Lymphocytes T; Macrophages; Mass Spectrometry; Medicine; Mice; Mice, Inbred C57BL; Monocytes - drug effects; Monocytes - pathology; Neutrophils; Pathogenesis; Peritonitis; Pharmacology; Receptor density; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - deficiency; Receptor, Cannabinoid, CB2 - metabolism; Recruitment; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling; Smooth muscle; T cells; Toxicology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0019405

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. Low density lipoprotein receptor-deficient (LDLR(-/-)) mice subjected to intraperitoneal injections of the selective CB(2) receptor agonist JWH-133 or vehicle three times per week consumed high cholesterol diet (HCD) for 16 weeks. Surprisingly, intimal lesion size did not differ between both groups in sections of the aortic roots and arches, suggesting that CB(2) activation does not modulate atherogenesis in vivo. Plaque content of lipids, macrophages, smooth muscle cells, T cells, and collagen were also similar between both groups. Moreover, CB(2) (-/-)/LDLR(-/-) mice developed lesions of similar size containing more macrophages and lipids but similar amounts of smooth muscle cells and collagen fibers compared with CB(2) (+/+)/LDLR(-/-) controls. While JWH-133 treatment reduced intraperitoneal macrophage accumulation in thioglycollate-elicited peritonitis, neither genetic deficiency nor pharmacologic activation of the CB(2) receptor altered inflammatory cytokine expression in vivo or inflammatory cell adhesion in the flow chamber in vitro. Our study demonstrates that both activation and deletion of the CB(2) receptor do not relevantly modulate atherogenesis in mice. Our data do not challenge the multiple reports involving CB(2) in other inflammatory processes. However, in the context of atherosclerosis, CB(2) does not appear to be a suitable therapeutic target for reduction of the atherosclerotic plaque.