ADVANCED GLYCATION END-PRODUCTS (AGES) ON THE SURFACE OF DIABETIC ERYTHROCYTES BIND TO THE VESSEL WALL VIA A SPECIFIC RECEPTOR INDUCING OXIDANT STRESS IN THE VASCULATURE - A LINK BETWEEN SURFACE-ASSOCIATED AGES AND DIABETIC COMPLICATIONS
ADVANCED GLYCATION END-PRODUCTS (AGES) ON THE SURFACE OF DIABETIC ERYTHROCYTES BIND TO THE VESSEL WALL VIA A SPECIFIC RECEPTOR INDUCING OXIDANT STRESS IN THE VASCULATURE - A LINK BETWEEN SURFACE-ASSOCIATED AGES AND DIABETIC COMPLICATIONS
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DOI：
10.1073/pnas.91.16.7742
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发表时间：
1994-08-02
影响因子：
11.1
通讯作者：
STERN, D
中科院分区：
文献类型：
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作者：
WAUTIER, JL;WAUTIER, MP;STERN, D
血管并发症是糖尿病患者发病率和死亡率的重要原因。从统计学上讲，血管并发症的程度与糖尿病红细胞与内皮细胞(ECs)的粘附性增强以及一类被称为晚期糖基化终产物(AGEs)的糖化蛋白的积累有关。我们假设糖尿病患者红细胞表面AGEs的形成可能介导了它们与内皮细胞的相互作用，从而导致结合和诱导血管功能障碍。用抗AGE抗体预先孵育红细胞或用抗AGE受体抗体(RAGE)预先孵育内皮细胞，可阻断糖尿病红细胞与内皮细胞的结合增强。培养的人内皮细胞的免疫印迹和正常/糖尿病人组织的免疫染色证实RAGE的存在是血管壁。糖尿病红细胞与内皮细胞的结合产生氧化应激，通过产生硫代巴比妥酸反应物质(TREs)和激活转录因子NF-kappa B来测量，这两者都被普罗布考或抗RAGE抗体阻断。将糖尿病大鼠的红细胞注入正常大鼠体内后，红细胞的早期清除速度加快，这在一定程度上是由RAGE抗体阻止的。输注糖尿病红细胞的大鼠肝组织中的TBARS水平升高，这种升高可被抗RAGE抗体或普罗布考预防。因此，红细胞表面AGEs可以作为配体与内皮细胞上的RAGE相互作用。携带表面相关糖基化终产物的糖尿病红细胞与血管壁RAGE的广泛接触可能在血管并发症的发生中起重要作用。
Vascular complications are an important cause of morbidity and mortality in patients with diabetes. The extent of vascular complications has been linked statistically to enhanced adherence of diabetic erythrocytes to endothelial cells (ECs) and to the accumulation of a class of glycated proteins termed advanced glycation end products (AGEs). We hypothesized that formation of AGEs on the surface of diabetic erythrocytes could mediate their interaction with ECs leading to binding and induction of vascular dysfunction. Enhanced binding of diabetic erythrocytes to ECs was blocked by preincubation of erythrocytes with anti-AGE IgG or preincubation of ECs with antibodies to the receptor for AGE (RAGE). Immunoblotting of cultured human ECs and immunostaining of normal/diabetic human tissue confirmed the presence of RAGE is the vessel wall. Binding of diabetic erythrocytes to endothelium generated an oxidant stress, as measured by production of thiobarbituric acid-reactive substances (TEARS) and activation of the transcription factor NF-kappa B, both of which were blocked by probucol or anti-RAGE IgG. Erythrocytes from diabetic rats infused into normal rats had an accelerated, early phase of clearance that was prevented, in part, by antibody to RAGE. Liver tissue from rats infused with diabetic erythrocytes showed elevated levels of TBARS, which was prevented by pretreatment with anti-RAGE IgG or probucol. Thus, erythrocyte surface AGEs can function as ligands that interact with RAGE on endothelium. The extensive contact of diabetic erythrocytes bearing surface-associated AGEs with vessel wall RAGE could be important in the development of vascular complications.