Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice
Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice
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DOI：
10.1172/jci32703
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发表时间：
2008-01-01
影响因子：
15.9
通讯作者：
Schmidt, Ann Marie
中科院分区：
文献类型：
--
作者：
Harja, Evis;Bu, De-Xiu;Schmidt, Ann Marie
内皮功能障碍是动脉粥样硬化的关键触发事件。脂蛋白进入血管壁后，其快速修饰导致晚期糖基化终产物表位的产生和随后的炎性细胞浸润。这些炎性细胞释放晚期糖基化终产物（AGEs）配体的受体，特别是S100/钙颗粒蛋白和高迁移率族蛋白1，它们维持血管损伤。在此，我们证明了apoE（-/-）小鼠动脉粥样硬化模型中，apoE及其配体在血管炎症、内皮功能障碍和动脉粥样硬化斑块发展中的关键作用。在从小鼠分离的原代主动脉内皮细胞和培养的人主动脉内皮细胞中的实验揭示了JNK信号传导在转导JNK配体对炎症的影响中的中心作用。这些数据强调了内皮RAGE及其配体介导血管和炎症应激的统一机制，最终导致脆弱血管壁的动脉粥样硬化。
Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE(-/-) mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall.