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

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PURPOSE: WIN55,212-2, a potent synthetic agonist of cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), reduces atherosclerosis in apolipoprotein E (ApoE) null mice. Although pharmacologic evidence suggests the anti-atherosclerotic effects of WIN55,212-2 are mediated CB2, this remains to be confirmed by genetic studies. Therefore, in this study, we investigated the effects of WIN55,212-2 on development of atherosclerosis in low-density lipoprotein receptor (Ldlr) null mice with and without homozygous deletion of the CB2 gene. METHODS: After 6 weeks on an atherogenic diet, groups of CB2 and CB2 Ldlr-null mice received a daily intraperitoneal injection of WIN55,212-2 or vehicle. After two weeks, plasma lipid levels and atherosclerosis in the aortic root were quantified. RESULTS: Plasma cholesterol and triglyceride levels did not differ between CB2 and CB2 mice and WIN55,212-2 had no effect on total cholesterol levels in either genotype. However, triglyceride levels in both CB2 and CB2 mice were significantly lowered by WIN55,212-2. The size of aortic root lesions did not differ significantly between CB2 and CB2 mice with or without WIN55,212-2 treatment. However, WIN55,212-2 treatment significantly lowered lesional macrophage accumulation in CB2 mice, and lesional smooth muscle content in both CB2 and CB2 mice. Lesional apoptosis was also greater in CB2 mice compared to CB2mice, and only reduced by WIN55,212-2 in CB2 mice. Collagen content and elastin fiber fragmentation were unaffected by genotype or WIN55,212-2. CONCLUSIONS: WIN55,212-2 treatment does not alter lesion size in Ldlr null-mice, but does modify lesion cellularity CB2-dependent and CB2-independent mechanisms.