Sengoelge G, Födinger M, Skoupy S, Ferrara I, Zangerle C, Rogy M, Hörl W H, Sunder-Plassmann G, Menzel J
Department of Internal Medicine III, Division of Nephrology, University of Vienna, Vienna, Austria.
Kidney Int. 1998 Nov;54(5):1637-51. doi: 10.1046/j.1523-1755.1998.00157.x.
Atherosclerotic vascular disease is the leading cause of death in patients with diabetes mellitus and end-stage renal disease. Advanced glycation end products (AGEs) are strongly suggested to be involved in the pathogenesis of atherosclerosis in these patients who also frequently experience infectious complications. We hypothesized that the interaction of AGEs and inflammatory mediators contributes to the up-regulation of endothelial cell activation.
We investigated the effect of advanced glycated fibronectin in the presence or absence of inflammatory stimuli on the endothelial cell surface and mRNA expression of cell adhesion molecules. Furthermore, the influence of advanced glycated fibronectin on the transendothelial migration pattern of polymorphonuclear cells was analyzed.
Exposure to advanced glycated fibronectin together with inflammatory stimuli such as interleukin (IL)-1alpha, tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) led to a significant increase in the surface expression of the cell adhesion molecules E-selectin, ICAM-1, VCAM-1 and PECAM-1 on endothelial cells. Soluble AGEs in combination with advanced glycated fibronectin significantly enhanced the endothelial cell surface expression of ICAM-1, VCAM-1 and PECAM-1, whereas this was not the case for E-selectin. At the transcriptional level short-time exposure of endothelial cells to advanced glycated fibronectin and inflammatory mediators resulted in an increased expression of E-selectin, ICAM-1 and VCAM-1 mRNA levels, whereas PECAM-1 repeatedly showed a significant decrease of gene transcript levels. An increase of mRNA levels was also observed for E-selectin, ICAM-1, VCAM-1 and PECAM-1 following incubation with a combination of advanced glycated fibronectin and soluble advanced glycation end-products. Furthermore, polymorphonuclear cells responded with a sevenfold increase in transendothelial migration following exposure of endothelial cells to advanced glycated fibronectin and inflammatory mediators.
These results suggest that the combination of matrix glycation and inflammation up-regulates the activation of the endothelial cell adhesion cascade, a mechanism that might contribute to the increased burden of atherosclerotic morbidity and mortality in patients suffering from diabetes mellitus or chronic renal failure.
动脉粥样硬化性血管疾病是糖尿病和终末期肾病患者的主要死因。晚期糖基化终产物（AGEs）被强烈认为参与了这些患者动脉粥样硬化的发病机制，而这些患者也经常发生感染并发症。我们推测AGEs与炎症介质的相互作用促成了内皮细胞活化的上调。
我们研究了在有或无炎症刺激的情况下，晚期糖基化纤连蛋白对内皮细胞表面及细胞黏附分子mRNA表达的影响。此外，还分析了晚期糖基化纤连蛋白对多形核细胞跨内皮迁移模式的影响。
暴露于晚期糖基化纤连蛋白并同时受到白细胞介素（IL）-1α、肿瘤坏死因子-α（TNF-α）或脂多糖（LPS）等炎症刺激，导致内皮细胞上细胞黏附分子E-选择素、细胞间黏附分子-1（ICAM-1）、血管细胞黏附分子-1（VCAM-1）和血小板内皮细胞黏附分子-1（PECAM-1）的表面表达显著增加。可溶性AGEs与晚期糖基化纤连蛋白联合使用可显著增强ICAM-1、VCAM-1和PECAM-1在内皮细胞表面的表达，而E-选择素则不然。在转录水平上，内皮细胞短期暴露于晚期糖基化纤连蛋白和炎症介质会导致E-选择素、ICAM-1和VCAM-1 mRNA水平增加，而PECAM-1的基因转录水平则反复显著下降。在用晚期糖基化纤连蛋白和可溶性晚期糖基化终产物联合孵育后，E-选择素、ICAM-1、VCAM-1和PECAM-1的mRNA水平也有所增加。此外，内皮细胞暴露于晚期糖基化纤连蛋白和炎症介质后，多形核细胞的跨内皮迁移增加了7倍。
这些结果表明，基质糖基化和炎症的联合作用上调了内皮细胞黏附级联反应的激活，这一机制可能导致糖尿病或慢性肾衰竭患者动脉粥样硬化发病率和死亡率增加。
