Cannabinoid receptor 2 signaling does not modulate atherogenesis in mice

Abstract

Background: Strong evidence supports a protective role of the cannabinoid receptor 2 (CB2) 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 CB2 receptor in Murine atherogenesis. Methods and Findings: Low density lipoprotein receptor-deficient (LDLR-/-) mice subjected to intraperitoneal injections of the selective CB2 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 CB2 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, CB2-/-/LDLR-/- mice developed lesions of similar size containing more macrophages and lipids but similar amounts of smooth muscle cells and collagen fibers compared with CB2+/+/LDLR-/- controls. While JWH-133 treatment reduced intraperitoneal macrophage accumulation in thioglycollate-illicited peritonitis, neither genetic deficiency nor pharmacologic activation of the CB2 receptor altered inflammatory cytokine expression in vivo or inflammatory cell adhesion in the flow chamber in vitro. Conclusion: Our study demonstrates that both activation and deletion of the CB2 receptor do not relevantly modulate atherogenesis in mice. Our data do not challenge the multiple reports involving CB2 in other inflammatory processes. However, in the context of atherosclerosis, CB2 does not appear to be a suitable therapeutic target for reduction of the atherosclerotic plaque. © 2011 Willecke et al.