TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice
TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice
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DOI：
10.1530/joe-12-0338
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发表时间：
2013-01-01
影响因子：
4
通讯作者：
Huang, Yan
中科院分区：
文献类型：
--
作者：
Lu, Zhongyang;Zhang, Xiaoming;Huang, Yan
尽管已有报道Toll样受体4(Toll-like Receptor 4，TLR4)的缺乏与动脉粥样硬化易感小鼠的动脉粥样硬化减轻和糖尿病小鼠的促炎状态减弱有关，但TLR4拮抗剂的治疗是否能减轻非糖尿病或糖尿病小鼠的动脉粥样硬化仍未确定。在这项研究中，我们测定了TLR4拮抗剂球形红杆菌脂多糖(Rs-LPS)对非糖尿病和链脲佐菌素诱导的糖尿病载脂蛋白E缺陷(APOE(-/-))小鼠早期动脉粥样硬化的影响。动脉粥样硬化病变的分析表明，14周龄糖尿病APOE(-/-)小鼠应用Rs-内毒素10周后，动脉粥样硬化病变明显减轻。尽管非糖尿病APOE(-/-)小鼠的动脉粥样硬化病变似乎通过Rs-内毒素治疗而减少，但差异并不具有统计学意义。代谢研究表明，Rs-LPS显著降低了非糖尿病小鼠的血清胆固醇和甘油三酯水平，但对糖尿病小鼠则没有。免疫组织化学研究显示，Rs-内毒素可抑制动脉粥样硬化斑块中白细胞介素6和基质金属蛋白酶-9的表达，减少单核细胞和巨噬细胞的含量。综上所述，这项研究首次证明TLR4拮抗剂抑制糖尿病APOE(-/-)小鼠的血管炎症和动脉粥样硬化形成，并降低非糖尿病APOE(-/-)小鼠的血清胆固醇和甘油三酯水平。
Although it has been reported that deficiency of toll-like receptor 4 (TLR4) is associated with reduced atherosclerosis in atherosclerosis-prone mice and attenuated pro-inflammatory state in diabetic mice, it remains undetermined whether treatment with a TLR4 antagonist reduces atherosclerosis in nondiabetic or diabetic mice that have TLR4 expression. In this study, we determined the effect of Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), an established TLR4 antagonist, on early-stage atherosclerosis in nondiabetic and streptozotocin-induced diabetic apolipoprotein E-deficient (Apoe(-/-)) mice. Analysis of atherosclerotic lesions of both en face aortas and cross sections of aortic roots showed that administration of Rs-LPS in 14-week-old diabetic Apoe(-/-) mice for 10 weeks significantly reduced atherosclerotic lesions. Although atherosclerotic lesions in nondiabetic Apoe(-/-) mice appeared to be decreased by Rs-LPS treatment, the difference was not statistically significant. Metabolic study showed that Rs-LPS significantly lowered serum levels of cholesterol and triglycerides in nondiabetic mice but not in diabetic mice. Furthermore, immunohistochemistry studies showed that Rs-LPS inhibited the expression of interleukin 6 and matrix metalloproteinase-9 and reduced the content of monocytes and macrophages in atherosclerotic plaques. Taken together, this study demonstrated for the first time that TLR4 antagonist inhibited vascular inflammation and atherogenesis in diabetic Apoe(-/-) mice and lowered serum cholesterol and triglyceride levels in nondiabetic Apoe(-/-) mice.