A hydroxyl radical-like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease

Recent evidence argues strongly that the marked increase in risk for athero sclerotic heart disease seen in diabetics cannot be explained by a generali zed increase in oxidative stress. Here, we used streptozotocin to induce hy perglycemia in cynomolgus monkeys for 6 months and tested whether high gluc ose levels promote localized oxidative damage to artery wall proteins. We f ocused on three potential agents of oxidative damage: hydroxyl radical, tyr osyl radical and reactive nitrogen species. To determine which pathways ope rate in vivo, we quantified four stable end products of these reactants - o rtho-tyrosine, meta-tyrosine, o,o'-dityrosine, and 3-nitrotyrosine - in aor tic 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 rad ical 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 sho rt-term hyperglycemia in primates promotes oxidation of artery wall protein s by a species that resembles hydroxyl radical. Our observations suggest th at glycoxidation reactions in the arterial microenvironment contribute to e arly diabetic vascular disease, raising the possibility that antioxidant th erapies might interrupt this process.