LXR激动剂对ApoE基因敲除小鼠动脉粥样硬化的作用

观察肝孤核受体（LXR）激动剂（T-0901317）对ApoE基因敲除小鼠［ApoE（-/-）］主动脉结构和血管活性的影响，探讨LXR激动剂对抑制动脉粥样硬化（AS）病变形成的作用及潜在机制。方法： 12周龄ApoE基因敲除小鼠随机分为AS模型对照组（AS组）与LXR激动剂干预组（AS＋LXR组），将有相同遗传背景的同龄正常C57BL/6J小鼠分为正常对照组（CON组）与单纯药物干预组（CON＋LXR组）。CON＋LXR组、AS＋LXR组LXR激动剂连续灌胃6周，剂量为10 mg/（kg·d）。AS组、CON组灌服等量生理盐水。各组小鼠在处理6周后进行外周血采集检测血脂，并分离主动脉, 透射电镜观察血管超微结构，Western blot测定主动脉壁中三磷酸腺苷结合盒转运体A1（ABCA1）蛋白的表达水平。结果： AS＋LXR组血浆总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）均显著低于AS组（P〈0.01）,高密度脂蛋白胆固醇（HDL-C）高于AS组（P〈0.05）。AS组主动脉内膜呈明显粥样硬化斑块形成特点，AS＋LXR组内皮变性坏死比AS组明显减低。与AS组比较，AS＋LXR组的AS病变面积显著降低,同时动脉壁中ABCA1的表达显著增强。结论： LXR激动剂T-0901317能够显著改善血脂，对主动脉内膜超微结构有良好的修复和保护作用，对高脂饲养的ApoE基因敲除小鼠的AS形成具有抑制作用，其作用机制可能与LXR激动剂上调动脉壁巨噬细胞中ABCA1蛋白的表达、增强胆固醇逆转运有关。

Effect of liver X-receptor agonist on atherosclerosis of apolipoprotein E-deficient mice

AIM： To observe the effects and mechanisms of liver X-receptor （LXR） agonist （T-0901317） on aorta structure, blood vessel activity and atheroselerosis in apolipoprotein E-deficient （ApoE-/-） mice. METHODS： Twelve-week-old ApoE-/- mice were divided randomly into model group （fed with saline, AS） and LXR agonist group （fed with LXR agonist, AS ＋ L） , and normal C57BL/6J mice were randomized into control group （fed with saline, C） and singlet intervention group （fed with LXR agonist, L）. LXR agonist （T-0901317） was orally administered daily at a dose of 10 mg/kg for 6 weeks. Plasma lipids were determined after 6 weeks treatment. Aortas were isolated and observed by transmission electron microscopy and expressions of ATP-binding cassette transporter AI （ ABCA1 ） in the aortic atherosclerotic lesions were detected by Western blot method. RESULTS： Levels of total cholesterol, triglyeeride and high-density lipoprotein cholesterol in AS ＋ L group were significantly lower than those in AS group （P 〈 0.05 ）. LXR agonist inhibited degeneration and necrosis of endothelium and significantly reversed the development of atheroselerotic lesions compared with that in AS group. Expressions of ABCA1 in the artery wall were elevated in AS ＋ L group compared with those in AS control. CONCLUSION： LXR agonist significantly decreases the level of serum lipids and reverses the development of atherosclerotic lesions in ApoE-/- mice. It is suggested that LXR agonist has favorable effects on artery endothelium repair, possibly by enhancing the reverse cholesterol transport in vivo via upregulating ABCA1 expression within the aorta wall.