Cannabinoid Receptor Type 2 (CB2) Dependent and Independent Effects of WIN55,212-2 on Atherosclerosis in Ldlr-null Mice.
Cannabinoid Receptor Type 2 (CB2) Dependent and Independent Effects of WIN55,212-2 on Atherosclerosis in Ldlr-null Mice.
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DOI：
10.12970/2311-052x.2015.03.02.2
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
Thewke D
中科院分区：
文献类型：
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作者：
Netherland-Van Dyke C;Rodgers W;Fulmer M;Lahr Z;Thewke D
WIN55,212-2 是 1 型大麻素受体 (CB1) 和 2 型大麻素受体 (CB2) 的有效合成激动剂，可减少载脂蛋白 E (ApoE) 缺失小鼠的动脉粥样硬化。尽管药理学证据表明 WIN55,212-2 的抗动脉粥样硬化作用是通过 CB2 介导的，但这仍有待基因研究证实。因此，在本研究中，我们研究了 WIN55,212-2 对具有和不具有 CB2 基因纯合缺失的低密度脂蛋白受体 (Ldlr) 缺失小鼠动脉粥样硬化发展的影响。采用致动脉粥样硬化饮食 6 周后，CB2+/+ 和 CB2−/− Ldlr-null 小鼠组每天接受 WIN55,212-2 或媒介物的腹膜内注射。两周后，对血浆脂质水平和主动脉根部的动脉粥样硬化进行了量化。 CB2+/+ 和 CB2−/− 小鼠之间的血浆胆固醇和甘油三酯水平没有差异，并且 WIN55,212-2 对任一基因型的总胆固醇水平没有影响。然而，WIN55,212-2 显着降低了 CB2+/+ 和 CB2−/− 小鼠的甘油三酯水平。在有或没有WIN55,212-2治疗的CB2+/+和CB2−/−小鼠之间，主动脉根部病变的大小没有显着差异。然而，WIN55,212-2治疗显着降低了CB2+/+小鼠中病变巨噬细胞的积累，以及CB2+/+和CB2−/−小鼠中病变平滑肌的含量。与CB2−/−小鼠相比，CB2+/+小鼠中的病变细胞凋亡也更大，并且仅在CB2+/+小鼠中被WIN55,212-2减少。胶原含量和弹性蛋白纤维断裂不受基因型或WIN55,212-2的影响。 WIN55,212-2治疗不会改变Ldlr无效小鼠的病变大小，但确实通过CB2依赖性和CB2独立机制改变病变细胞结构。
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. 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. 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. 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.