Cannabinoid receptor type 2 (CB2) deficiency alters atherosclerotic lesion formation in hyperlipidemic Ldlr-null mice

Abstract

Objective-To determine if cannabinoid receptor 2 (CB2) plays a role in atherosclerosis, we investigated the effects of systemic CB2 gene deletion on hyperlipidemia-induced atherogenesis in low density lipoprotein receptor-deficient (Ldlr −/− ) mice.Methods and results-Ldlr −/− and CB2/Ldlr double knockout (CB2 −/− Ldlr −/− ) mice were fed an atherogenic diet for 8 and 12 weeks. Morphometric analysis revealed no significant difference between the atherosclerotic lesion area in the proximal aortas of Ldlr −/− and CB2 −/− Ldlr −/− mice after 8 or 12 weeks on the atherogenic diet. The macrophage and smooth muscle cell (SMC) content, as revealed by immunohistochemical staining, did not differ significantly between Ldlr −/− and CB2 −/− Ldlr −/− lesions after 8 weeks. However, after 12 weeks, CB2 −/− Ldlr −/− lesions displayed greater macrophage content (86.6 ± 4.1 versus 75.2 ± 7.5%, P < 0.05) and SMC content (11.1 ± 5.1 versus 4.2 ± 2.4%, P < 0.05) compared to controls. Lesional apoptosis, as determined by in situ TUNEL analysis, was reduced ∼50% in CB2 −/− Ldlr −/− lesions after 12 weeks. CB2 −/− Ldlr −/− lesions displayed significantly reduced collagen content and increased elastin fiber fragmentation after 12 weeks, which was associated with an ∼57% increase in matrix metalloproteinase 9 (MMP) levels. In vitro, CB2 −/− macrophages secreted ∼1.8-fold more MMP9 activity than CB2 +/+ macrophages. Conclusions-CB2receptor deficiency affects atherogenesis in Ldlr-null mice by increasing lesional macrophage and SMC content, reducing lesional apoptosis and altering extracellular matrix components, in part, by upregulating MMP9. These results suggest that pharmacological manipulation of CB2 receptors might exert multiple and complex effects on atherogenesis and plaque stability.

Cannabinoid receptor CB2 protects against balloon-induced neointima formation

“…We and others (15,26,35,40,41) previously provided experimental evidence on a possible role of CB 2 receptors in atherogenesis.…”

“…CB 2 receptors are expressed on arterial endothelial and smooth muscle cells and immune cells (27). There is accumulating evidence that activation of CB 2 receptors with endogenous or synthetic ligands limits inflammatory responses such as endothelial activation, immune cell adhesion, and migration, which are relevant for the pathogenesis of atherosclerosis and restenosis (4,23,26,29,35,40,41).…”

Endocannabinoids and the Cardiovascular System in Health and Disease

“…Mice in which the CB 1 receptor has been knocked-out are more susceptible to chronic heart failure (Liao et al 2013), and stroke . CB 2 -deficient mice have increased susceptibility to atherosclerosis (Netherland et al 2010;Hoyer et al 2011), stroke (Zhang et al 2008) and cardiomyopathy (Duerr et al 2014). …”

Cannabinoid Receptor Type 2 (CB2) Dependent and Independent Effects of WIN55,212-2 on Atherosclerosis in Ldlr-null Mice

“…In addition to their well-known psychotropic effects, cannabinoids exert immunosuppressive and anti-inflammatory effects, leading to the suggestion that cannabinoids may prove beneficial in the treatment of inflammatory disorders [3–6] and atherosclerosis [7–12]. Cannabinoids produce their effects primarily through binding of two G-protein coupled receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2).…”