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

Abstract

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.

The CB2 receptor and its role as a regulator of inflammation

“…However, a few reports show conflicting data, especially in the Ldlr − / − model. A report shows unaltered lesion size following WIN 55,212-2 treatment in this model, although CB 2 receptor activation did decrease lesional macrophage accumulation [ 192 ]. Another group treated Ldlr − / − mice with JWH-133 and found no significant effect on lesion size or on their content in macrophages, lipids, smooth muscle cells, collagen, and T cells [ 193 ].…”

Prospects for the Use of Cannabinoid Receptor Ligands for the Treatment of Metabolic Syndrome and Atherosclerosis: Analysis of Experimental and Clinical Data

“…Антиатерогенный эффект JWH015 исчезал после применения селективного CB2-антагониста SR144528, из чего следует, что этот эффект связан с активацией CB2-рецепторов макрофагов. Исследователи из США попытались выяснить, действительно ли антиатерогенный эффект WIN55212-2 связан с активацией CB2рецепторов [47]. Исследования они проводили на мышах LDLR(-/-) с нормальной экспрессией CB2-рецептора генотип CB(+/+) и с делецией гена CB2-рецептора генотип CB2(-/-).…”

“…Однако WIN55212-2 снижал количество макрофагов в бляшках у мышей CB2(+/+), но не влиял на аккумуляцию ма-крофагов в атеромах у животных с генотипом CB2(-/-). В то же время WIN55212-2 снижал количество гладкомышечных клеток в атеромах обеих групп мышей [47]. Следовательно, эффекты WIN55212-2 могут зависеть от активации CB2-рецепторов и реализовываться независимо от указанных рецепторов.…”

“…[45] и C. Netherland-Van Dyke и соавт. [47]. Следовательно, эндогенные агонисты CB2-рецепторов не влияют на формирование атеросклеротических бляшек.…”

“…Оказалось, что у CB2(-/-)-реципиентов размер атеросклеротической бляшки больше, чем у CB2(+/+)-реципиентов, что позволило авторам сделать вывод, что эндогенные агонисты CB2-рецепторов препятствуют атерогенезу. Однако результаты других исследований не подтверждают эту точку зрения [45,47,48].…”