Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, China.
Eur J Pharmacol. 2010 Dec 15;649(1-3):285-92. doi: 10.1016/j.ejphar.2010.09.027. Epub 2010 Sep 21.
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 CB₂ receptor.
炎症在动脉粥样硬化的各个阶段都发挥着重要作用，人们积极研究其作用机制，以期发现新型创新药物用于治疗和预防。大麻素具有抗炎和免疫调节作用，在包括心血管疾病在内的各种炎症性疾病中有广泛的治疗潜力。本研究旨在探讨合成大麻素 WIN55212-2 对胆酸盐高脂饮食喂养的载脂蛋白 E 基因敲除（ApoE(-/-)）小鼠动脉粥样硬化的影响。我们的结果表明，WIN55212-2 可减小主动脉根部粥样硬化病变的大小，但对血清脂质水平无显著影响。此外，WIN55212-2 减轻动脉粥样硬化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 激活减少有关。氧化型 LDL（ox-LDL）可显著诱导 NF-κB 激活，并增强 ApoE(-/-) 小鼠腹腔巨噬细胞中促炎 mRNA 和蛋白的表达。值得注意的是，ox-LDL 的上述所有作用均被 WIN55212-2 减弱。此外，WIN55212-2 还可减轻 LPS 诱导的炎症反应。大麻素受体 2（CB₂）特异性拮抗剂 AM630 完全消除了 WIN55212-2 在体内和体外的保护作用。我们的数据提供了有力的证据，表明 WIN55212-2 可抑制 ApoE(-/-) 小鼠的动脉粥样硬化。重要的是，WIN55212-2 在我们模型中的所有有益作用都与抑制促炎反应密切相关，并且由 CB₂ 受体介导。
