WIN55212-2 ameliorates atherosclerosis associated with suppression of pro-inflammatory responses in ApoE-knockout mice.
WIN55212-2 ameliorates atherosclerosis associated with suppression of pro-inflammatory responses in ApoE-knockout mice.
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DOI：
10.1016/j.ejphar.2010.09.027
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发表时间：
2010-12
影响因子：
5
通讯作者：
Yan Zhao;Yan Liu;Wei-ping Zhang;Jiahong Xue;Yue Wu;Wei Xu;X. Liang;Tao Chen;C. Kishimoto;Zuyi Yuan
中科院分区：
文献类型：
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作者：
Yan Zhao;Yan Liu;Wei-ping Zhang;Jiahong Xue;Yue Wu;Wei Xu;X. Liang;Tao Chen;C. Kishimoto;Zuyi Yuan
炎症在动脉粥样硬化各个阶段的作用已被积极研究，重点是发现用于治疗和预防的新型和创新药物。大麻素的抗炎和免疫调节能力已得到充分证实，这些药物在各种炎症性疾病（包括心血管疾病）中具有广泛的治疗潜力。本研究的目的是研究WIN 55212 -2（一种合成大麻素）对载脂蛋白E基因敲除（ApoE−/−）小鼠动脉粥样硬化的影响，该小鼠接受含胆酸盐的高脂肪饮食。我们的研究结果表明，WIN 55212 -2减少了主动脉根部动脉粥样硬化病变的大小，并没有影响血脂水平显着。此外，WIN 55212 -2对动脉粥样硬化的缓解与斑块病变中巨噬细胞含量减少以及主动脉组织中促炎基因表达和NF-κB活化降低有关。氧化低密度脂蛋白（ox-LDL）显著诱导NF-κB活化，并增强从ApoE−/−小鼠分离的腹腔巨噬细胞中的促炎mRNA和蛋白表达。值得注意的是，WIN 55212 -2减弱了ox-LDL的所有上述作用。此外，WIN 55212 -2还减轻了LPS诱导的炎症反应。大麻素受体2（CB 2）特异性拮抗剂AM 630可完全阻断WIN 55212 -2的保护作用。我们的数据提供了强有力的证据，证明WIN 55212 -2可以潜在地抑制ApoE−/−小鼠的动脉粥样硬化。重要的是，WIN 55212 -2在我们的模型中的所有有益作用都与抑制促炎反应密切相关，并由CB 2受体介导。
The role of inflammation in all stages of atherosclerosis has been actively investigated, with an emphasis on the discovery of novel and innovative drugs for treatment and prevention. The anti-inflammatory and immunomodulatory capacity of cannabinoids are well established, and these agents have a broad therapeutic potential in various inflammatory diseases, including cardiovascular diseases. The aim of this study was to investigate the effect of WIN55212-2, a synthetic cannabinoid, on atherosclerosis using the apolipoprotein E-knockout (ApoE−/−) mouse on a cholate-containing high-fat diet. Our results showed that WIN55212-2 reduced the size of atherosclerotic lesions in the aorta root, and did not affect serum lipid levels significantly. Furthermore, alleviation of atherosclerosis by WIN55212-2 was associated with a smaller content of macrophages in plaque lesion as well as decreasing pro-inflammatory gene expression and NF-κB activation in aortic tissues. Oxidized LDL (ox-LDL) dramatically induced NF-κB activation, and enhanced pro-inflammatory mRNA and protein expression in peritoneal macrophages isolated from ApoE−/−mice. It is noteworthy that all of the above-mentioned effects of ox-LDL were attenuated by WIN55212-2. Moreover, WIN55212-2 also attenuated the inflammatory response that LPS induced. AM630, a cannabinoid receptor 2 (CB2) special antagonist completely abolished the protective effects of WIN55212-2 both in vivo and in vitro. Our data provide strong evidence that WIN55212-2 can potentially inhibit atherosclerosis in ApoE−/−mice. Importantly, all the beneficial effects of WIN55212-2 in our model were closely associated with the suppression of pro-inflammatory responses and were mediated by the CB2receptor.