Interactions of copper with glycated proteins: Possible involvement in the etiology of diabetic neuropathy
Interactions of copper with glycated proteins: Possible involvement in the etiology of diabetic neuropathy
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DOI：
10.1023/a:1015988817587
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发表时间：
2002-05-01
影响因子：
4.3
通讯作者：
Qian, MW
中科院分区：
文献类型：
--
作者：
Eaton, JW;Qian, MW
患有糖尿病的人和动物经常会出现周围血管功能障碍和周围神经病变。越来越多的证据表明，周围神经功能受损可能源于神经内血流减少。神经血流量的减少可能是由于内皮依赖性血管扩张功能减弱所致。虽然已经提出了这种有缺陷的血管扩张的一些可能的原因，但没有一个得到明确的证实。无论确切原因如何，血管扩张活性受损可能反映内皮源性松弛因子(EDRF)的可获得性降低，不同的人认为EDRF是一氧化氮或一氧化氮的硫醇加合物。其他研究人员已经报道，给糖尿病大鼠注射过渡金属螯合剂可以纠正EDRF介导的动脉松弛，并恢复神经血流量和神经传导速度，这表明过渡金属参与其中。我们的研究集中在这样一种假设上，即糖化蛋白与铜和铁等过渡金属结合，这种‘糖络合物’在糖尿病患者的血管内积累，并催化使EDRF失活。部分支持这一假设的是：(1)糖化白蛋白与铜和铁的结合量增加了3倍。(2)与糖化白蛋白结合的铜保持氧化还原活性(例如，能够支持抗坏血酸的氧化)。(3)铜和含铜的糖络合物导致EDRF的一种可能形式亚硝基半胱氨酸的快速分解。(4)糖尿病大鼠血浆中可交换(即可螯合)铜的含量约为正常大鼠血浆的两倍。(5)同样，糖尿病动物的尾部肌腱的结合铜含量大约是正常大鼠肌腱的两倍。(6)含糖化白蛋白的种植体在正常小鼠腹膜内放置48h，其结合态铜的积累量是包被对照白蛋白的种植体的5倍。总体而言，这些观察结果支持-但不是最终证明--过渡金属，如铜，与糖化蛋白结合，可能会削弱糖尿病动脉正常的EDRF依赖的松弛，并为在糖尿病血管病变和神经病变的治疗中使用过渡金属螯合剂提供了理论基础。
Humans and animals with diabetes frequently develop peripheral vascular dysfunction and peripheral neuropathies. There is accumulating evidence that impaired peripheral nerve function may derive from diminished endoneural blood flow. The decrements in nerve blood flow may, in turn, be due to diminished endothelium-dependent vasodilation. Although a number of possible causes of this defective vasodilation have been suggested, none has been definitely proven. Regardless of the precise cause, the impaired vasodilatory activity may reflect diminished availability of endothelium-derived relaxing factor (EDRF), variously thought to be nitric oxide or thiol adducts of nitric oxide. Other investigators have reported that administration of transition metal chelators to diabetic rats corrects EDRF-mediated arterial relaxation and restores both neural blood flow and nerve conduction velocity, suggesting the involvement of transition metals. Our investigations center about the hypothesis that glycated proteins bind transition metals such as copper and iron, and that such 'glycochelates' accumulate within the vasculature in diabetes and catalytically inactivate EDRF. In partial support of this hypothesis: (1) Glycated albumin binds 3-fold greater amounts of both copper and iron. (2) Copper bound to glycated albumin remains redox active (e.g. capable of supporting the oxidation of ascorbic acid). (3) Copper and copper-containing glycochelates cause the rapid decomposition of one putative form of EDRF, nitrosocysteine. (4) The amount of exchangeable (i.e. chelatable) copper in the plasma of diabetic rats is approximately twice that in normal rat plasma. (5) Similarly, tail tendons of diabetic animals have about twice as much bound copper as do tendons of normal rats. (6) Implants bearing adsorbed glycated albumin placed in the peritonea of normal mice for 48 h accumulate 5 times as much bound copper as do implants coated with control albumin. Overall, these observations support - but do not conclusively prove - the hypothesis that transition metals such as copper, bound to glycated proteins, may blunt normal EDRF-dependent relaxation of diabetic arteries and provide a rationale for the use of transition metal chelators in the therapy of diabetic vasculopathy and neuropathy.