Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage
Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage
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DOI：
10.1038/35008121
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发表时间：
2000-04-13
期刊：
影响因子：
64.8
通讯作者：
Brownlee, M
中科院分区：
文献类型：
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作者：
Nishikawa, T;Edelstein, D;Brownlee, M
糖尿病高血糖可引起小血管、动脉和周围神经的多种病理改变(1)。血管内皮细胞是高血糖损伤的重要靶点，但这种损伤的机制尚不完全清楚。三种看似独立的生化途径参与了发病机制：葡萄糖诱导的蛋白激酶C亚型的激活(2)；葡萄糖衍生的晚期糖基化终产物的形成增加(3)；通过醛糖还原酶途径增加葡萄糖通量(4)。每种途径的相关性都得到了动物研究的支持，在这些研究中，途径特异性抑制剂可以预防各种高血糖诱导的异常（3,5-7）。高血糖增加了培养的牛主动脉内皮细胞内活性氧的产生(8)。在这里，我们表明这种活性氧的增加被电子传递链复合物II的抑制剂、氧化磷酸化的解偶联剂、解偶联蛋白-1和锰超氧化物歧化酶所阻止。用这些药物使线粒体活性氧水平正常化，可以防止葡萄糖诱导的蛋白激酶C的激活、晚期糖基化终产物的形成、山梨醇积累和NF κ B的激活。
Diabetic hyperglycaemia causes a variety of pathological changes in small vessels, arteries and peripheral nerves(1). Vascular endothelial cells are an important target of hyperglycaemic damage, but the mechanisms underlying this damage are not fully understood. Three seemingly independent biochemical pathways are involved in the pathogenesis: glucose-induced activation of protein kinase C isoforms(2); increased formation of glucose-derived advanced glycation end-products(3); and increased glucose flux through the aldose reductase pathway(4). The relevance of each of these pathways is supported by animal studies in which pathway-specific inhibitors prevent various hyperglycaemia-induced abnormalities(3,5-7). Hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells(8). Here we show that this increase in reactive oxygen species is prevented by an inhibitor of electron transport chain complex II, by an uncoupler of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide dismutase. Normalizing levels of mitochondrial reactive oxygen species with each of these agents prevents glucose-induced activation of protein kinase C, formation of advanced glycation end-products, sorbitol accumulation and NF kappa B activation.