Yan S D, Schmidt A M, Anderson G M, Zhang J, Brett J, Zou Y S, Pinsky D, Stern D
Department of Physiology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
J Biol Chem. 1994 Apr 1;269(13):9889-97.
Attack by reactive oxygen intermediates, common to many kinds of cell/tissue injury, has been implicated in the development of diabetic and other vascular diseases. Such oxygen-free radicals can be generated by advanced glycation end products (AGEs), which are nonenzymatically glycated and oxidized proteins. Since cellular interactions of AGEs are mediated by specific cellular binding proteins, receptor for AGE (RAGE) and the lactoferrin-like polypeptide (LF-L), we tested the hypothesis that AGE ligands tethered to the complex of RAGE and LF-L could induce oxidant stress. AGE albumin or AGEs immunoisolated from diabetic plasma resulted in induction of endothelial cell (EC) oxidant stress, including the generation of thiobarbituric acid reactive substances (TBARS) and resulted in the activation of NF-kappa B, each of which was blocked by antibodies to AGE receptor polypeptides and by antioxidants. Infusion of AGE albumin into normal animals led to the appearance of malondialdehyde determinants in the vessel wall and increased TBARS in the tissues, activation of NF-kappa B, and induction of heme oxygenase mRNA. AGE-induced oxidant stress was inhibited by pretreatment of animals with either antibodies to the AGE receptor/binding proteins or antioxidants. These data indicate that interaction of AGEs with cellular targets, such as ECs, leads to oxidant stress resulting in changes in gene expression and other cellular properties, potentially contributing to the development of vascular lesions. Further studies will be required to dissect whether oxidant stress occurs on the cell surface or at an intracellular locus.
活性氧中间体攻击是多种细胞/组织损伤的共同特征，已被认为与糖尿病及其他血管疾病的发生有关。这种氧自由基可由晚期糖基化终产物（AGEs）产生，AGEs是经非酶糖基化和氧化的蛋白质。由于AGEs与细胞的相互作用是由特定的细胞结合蛋白，即AGE受体（RAGE）和乳铁蛋白样多肽（LF-L）介导的，我们检验了这样一个假说，即与RAGE和LF-L复合物相连的AGE配体可诱导氧化应激。从糖尿病血浆中免疫分离出的AGE白蛋白或AGEs可诱导内皮细胞（EC）氧化应激，包括硫代巴比妥酸反应性物质（TBARS）的生成，并导致核因子κB（NF-κB）活化，而这两者均被AGE受体多肽抗体和抗氧化剂所阻断。向正常动物输注AGE白蛋白会导致血管壁中出现丙二醛测定值，组织中TBARS增加，NF-κB活化以及血红素加氧酶mRNA的诱导。用AGE受体/结合蛋白抗体或抗氧化剂对动物进行预处理可抑制AGE诱导的氧化应激。这些数据表明，AGEs与细胞靶点（如内皮细胞）的相互作用会导致氧化应激，从而引起基因表达和其他细胞特性的改变，这可能对血管病变发展有促进作用。还需要进一步研究来剖析氧化应激是发生在细胞表面还是细胞内位点。
