RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice
RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice
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DOI：
10.1161/01.cir.0000039325.03698.36
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发表时间：
2002-11-26
期刊：
影响因子：
37.8
通讯作者：
Schmidt, AM
中科院分区：
文献类型：
--
作者：
Bucciarelli, LG;Wendt, T;Schmidt, AM
背景-先前的研究表明，阻断糖尿病载脂蛋白E缺失小鼠的RAGE可抑制动脉粥样硬化的早期加速。RAGE阻断在临床环境中的潜在适用性的一个关键测试是它影响已建立的血管疾病的能力。在这项研究中，我们测试了RAGE在糖尿病apoE基因缺失小鼠已建立的动脉粥样硬化中促进病变进展的假设。方法和结果-6周龄的雄性apoE基因缺失小鼠用链脲佐菌素或柠檬酸缓冲液治疗糖尿病。在14周龄时，某些小鼠被处死，或用每天一次的小鼠可溶性RAGE或白蛋白治疗；所有小鼠在20周龄时被处死。与14周龄的糖尿病小鼠相比，白蛋白治疗的小鼠表现出更大的动脉粥样硬化病变面积和复杂性。在14至20周使用SRAGE治疗的糖尿病小鼠中，病变面积和复杂性显著减少，与14周时观察到的糖尿病小鼠没有统计学差异。同时观察到炎症参数、单核巨噬细胞和平滑肌细胞激活的降低。结论RAGE不仅促进了糖尿病apoE基因缺失小鼠病变的形成，而且促进了病变的进展。阻断RAGE可能是稳定糖尿病患者动脉粥样硬化和血管炎症的新策略。
Background-Previous studies suggested that blockade of RAGE in diabetic apolipoprotein (apo) E-null mice suppressed early acceleration of atherosclerosis. A critical test of the potential applicability of RAGE blockade to clinical settings was its ability to impact established vascular disease. In this study, we tested the hypothesis that RAGE contributed to lesion progression in established atherosclerosis in diabetic apoE-null mice.Methods and Results-Male apoE-null mice, age 6 weeks, were rendered diabetic with streptozotocin or treated with citrate buffer. At age 14 weeks, certain mice were killed or treated with once-daily murine soluble RAGE or albumin; all mice were killed at age 20 weeks. Compared with diabetic mice at age 14 weeks, albumin-treated animals displayed increased atherosclerotic lesion area and complexity. In diabetic mice treated with sRAGE from age 14 to 20 weeks, lesion area and complexity were significantly reduced and not statistically different from those observed in diabetic mice at age 14 weeks. In parallel, decreased parameters of inflammation and mononuclear phagocyte and smooth muscle cell activation were observed.Conclusions-RAGE contributes not only to accelerated lesion formation in diabetic apoE-null mice but also to lesion progression. Blockade of RAGE may be a novel strategy to stabilize atherosclerosis and vascular inflammation in established diabetes.