ADVANCED GLYCATION ENDPRODUCTS INTERACTING WITH THEIR ENDOTHELIAL RECEPTOR INDUCE EXPRESSION OF VASCULAR CELL-ADHESION MOLECULE-1 (VCAM-1) IN CULTURED HUMAN ENDOTHELIAL-CELLS AND IN MICE - A POTENTIAL MECHANISM FOR THE ACCELERATED VASCULOPATHY OF DIABETES
ADVANCED GLYCATION ENDPRODUCTS INTERACTING WITH THEIR ENDOTHELIAL RECEPTOR INDUCE EXPRESSION OF VASCULAR CELL-ADHESION MOLECULE-1 (VCAM-1) IN CULTURED HUMAN ENDOTHELIAL-CELLS AND IN MICE - A POTENTIAL MECHANISM FOR THE ACCELERATED VASCULOPATHY OF DIABETES
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DOI：
10.1172/jci118175
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发表时间：
1995-09-01
影响因子：
15.9
通讯作者：
STERN, D
中科院分区：
文献类型：
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作者：
SCHMIDT, AM;HORI, O;STERN, D
血管细胞粘附分子-1（VCAM-1）是内皮细胞表面的一种可诱导的细胞-细胞识别蛋白，与动脉粥样硬化的早期阶段有关。鉴于在糖尿病患者中观察到的加速的血管疾病，以及糖尿病兔中VCAM-1表达的增强，我们检测了不可逆的晚期糖基化终产物（AGEs）是否可以通过与其内皮细胞受体相互作用介导VCAM-1的表达（AGE的受体，VEGF），将培养的人EC暴露于AGE诱导VCAM-1的表达，增加Molt-4细胞单层的粘附性，并且与VCAM-1转录水平的增加有关。抗VCAM-1 IgG的抑制作用，（可溶性半胱氨酸）或N-乙酰半胱氨酸对VCAM-1表达的影响表明AGE-CYP诱导的氧化应激是VCAM-1诱导的中心，电泳迁移率变动分析表明，从AGE处理的EC的核提取物的诱导特异性DNA结合活性的NF-LB在VCAM-1中，1启动子的启动子区，该启动子区可被抗人IgG或N-乙酰半胱氨酸阻断。可溶性VCAM-1抗原在人糖尿病血浆中升高。这些数据与以下假设一致，即AGE-β相互作用诱导VCAM-1的表达，VCAM-1可以引发糖尿病血管系统与循环单核细胞的增强的相互作用。
Vascular cell adhesion molecule-1 (VCAM-1), an inducible cell-cell recognition protein on the endothelial cell surface (EC), has been associated with early stages of atherosclerosis. In view of the accelerated vascular disease observed in patients with diabetes, and the enhanced expression of VCAM-1 in diabetic rabbits, we examined whether irreversible advanced glycation endproducts (AGEs), could mediate VCAM-1 expression by interacting with their endothelial cell receptor (receptor for AGE, RAGE), Exposure of cultured human ECs to AGEs induced expression of VCAM-1, increased adhesivity of the monolayer for Molt-4 cells, and was associated with increased levels of VCAM-1 transcripts, The inhibitory effect of anti-RAGE IgG, a truncated form of the receptor (soluble RAGE) or N-acetylcysteine on VCAM-1 expression indicated that AGE-RAGE-induced oxidant stress was central to VCAM-1 induction, Electrophoretic mobility shift assays on nuclear extracts from AGE-treated ECs showed induction of specific DNA binding activity for NF-LB in the VCAM-1 promoter, which was blocked by anti-RAGE IgG or N-acetylcysteine. Soluble VCAM-1 antigen was elevated in human diabetic plasma, These data are consistent with the hypothesis that AGE-RAGE interaction induces expression of VCAM-1 which can prime diabetic vasculature for enhanced interaction with circulating monocytes.