Pennathur S, Wagner J D, Leeuwenburgh C, Litwak K N, Heinecke J W
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
J Clin Invest. 2001 Apr;107(7):853-60. doi: 10.1172/JCI11194.
Recent evidence argues strongly that the marked increase in risk for atherosclerotic heart disease seen in diabetics cannot be explained by a generalized increase in oxidative stress. Here, we used streptozotocin to induce hyperglycemia in cynomolgus monkeys for 6 months and tested whether high glucose levels promote localized oxidative damage to artery wall proteins. We focused on three potential agents of oxidative damage: hydroxyl radical, tyrosyl radical, and reactive nitrogen species. To determine which pathways operate in vivo, we quantified four stable end products of these reactants -- ortho-tyrosine, meta-tyrosine, o,o'-dityrosine, and 3-nitrotyrosine -- in aortic proteins. Levels of ortho-tyrosine, meta-tyrosine, and o,o'-dityrosine, but not of 3-nitrotyrosine, were significantly higher in aortic tissue of hyperglycemic animals. Of the oxidative agents we tested, only hydroxyl radical mimicked this pattern of oxidized amino acids. Moreover, tissue levels of ortho-tyrosine and meta-tyrosine correlated strongly with serum levels of glycated hemoglobin, a measure of glycemic control. We conclude that short-term hyperglycemia in primates promotes oxidation of artery wall proteins by a species that resembles hydroxyl radical. Our observations suggest that glycoxidation reactions in the arterial microenvironment contribute to early diabetic vascular disease, raising the possibility that antioxidant therapies might interrupt this process.
近期证据有力地表明，糖尿病患者动脉粥样硬化性心脏病风险的显著增加无法用氧化应激的普遍增加来解释。在此，我们用链脲佐菌素使食蟹猴发生高血糖6个月，并测试高血糖水平是否会促进动脉壁蛋白的局部氧化损伤。我们聚焦于三种潜在的氧化损伤介质：羟自由基、酪氨酰自由基和活性氮物质。为确定体内起作用的是哪些途径，我们对主动脉蛋白中这些反应物的四种稳定终产物——邻酪氨酸、间酪氨酸、邻，邻'-二酪氨酸和3-硝基酪氨酸进行了定量。高血糖动物主动脉组织中邻酪氨酸、间酪氨酸和邻，邻'-二酪氨酸的水平显著升高，但3-硝基酪氨酸的水平未升高。在我们测试的氧化介质中，只有羟自由基模拟了这种氧化氨基酸的模式。此外，邻酪氨酸和间酪氨酸的组织水平与糖化血红蛋白的血清水平密切相关，糖化血红蛋白是血糖控制的一个指标。我们得出结论，灵长类动物的短期高血糖通过一种类似于羟自由基的物质促进动脉壁蛋白的氧化。我们的观察结果表明，动脉微环境中的糖氧化反应促成了早期糖尿病血管疾病，这增加了抗氧化疗法可能中断这一过程的可能性。
