Harja Evis, Bu De-xiu, Hudson Barry I, Chang Jong Sun, Shen Xiaoping, Hallam Kellie, Kalea Anastasia Z, Lu Yan, Rosario Rosa H, Oruganti Sai, Nikolla Zana, Belov Dmitri, Lalla Evanthia, Ramasamy Ravichandran, Yan Shi Fang, Schmidt Ann Marie
Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, New York 10032, USA.
J Clin Invest. 2008 Jan;118(1):183-94. doi: 10.1172/JCI32703.
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.
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，其快速修饰会导致晚期糖基化终末产物表位的产生以及随后炎症细胞的浸润。这些炎症细胞释放晚期糖基化终末产物受体（RAGE）配体，特别是S100/钙粒蛋白和高迁移率族蛋白B1，它们会持续造成血管损伤。在此，我们在动脉粥样硬化小鼠模型apoE-/-小鼠中证明了RAGE及其配体在血管炎症、内皮功能障碍和动脉粥样硬化斑块形成中的关键作用。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实验揭示了JNK信号在传导RAGE配体对炎症的影响中的核心作用。这些数据突出了统一的机制，即内皮RAGE及其配体介导血管和炎症应激，最终在易损血管壁中导致动脉粥样硬化。
