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

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 via 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 CB2^-/-mice, 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 via CB2-dependent and CB2-independent mechanisms.