Ceriello Antonio
University of Udine, Italy.
Int J Clin Pract Suppl. 2002 Jul(129):51-8.
Oxidative stress plays an important role in diabetic vascular complications. It has been shown that an imbalance in the ratio of nitric oxide to superoxide anion due to a prevalence of the superoxide anion leads to an alteration in vascular reactivity. Under these conditions an increase in peroxynitrite (ONOO-) production, resulting from the reaction between nitric oxide (NO) and superoxide (O2-), may be hypothesised. ONOO- is responsible for nitration of tyrosine residues in proteins; therefore the presence of nitrotyrosine (NT) in plasma proteins is considered indirect evidence of ONOO- production. NT has been found in the plasma of patients with diabetes, but it is not detectable in the plasma of healthy controls. NT plasma values are correlated with plasma glucose concentrations, and further studies exploring the effects of acute hyperglycaemia on NT formation confirmed that NT is produced both in normal subjects during hyperglycaemic clamp and in working hearts from rats during hyperglycaemic perfusion. Postprandial hypertriglyceridemia and hyperglycaemia are considered risk factors for cardiovascular disease. Evidence suggests that postprandial hypertriglyceridaemia and hyperglycaemia induce an endothelial dysfunction through an oxidative stress; however, the specific roles of these two factors are matters for debate. In a clinical study, high-fat load and glucose alone each produced a decrease in endothelial function and an increase in NT in normal subjects and patients with diabetes. These effects were more pronounced when high-fat load and glucose were combined. Short-term simvastatin treatment had no effect on lipid parameters, but reduced the effects of high-fat load, glucose alone, and both high-fat load and glucose on endothelial function and NT Long-term simvastatin treatment was accompanied by a smaller increase in postprandial triglycerides, which was followed by smaller variations in endothelial function and NT. This study showed an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycaemia on endothelial function, suggesting oxidative stress as a common mediator of these effects. Simvastatin shows a beneficial effect on oxidative stress and endothelial dysfunction, which may be ascribed to a direct effect as well as the lipid-lowering action of the drug. These studies indicate that ONOO- is generated in diabetes, suggesting the possible involvement of ONOO- in the development of diabetic complications.
氧化应激在糖尿病血管并发症中起重要作用。研究表明，由于超氧阴离子占优势，一氧化氮与超氧阴离子的比例失衡会导致血管反应性改变。在这些情况下，可以推测一氧化氮（NO）与超氧阴离子（O2-）反应会导致过氧亚硝酸盐（ONOO-）生成增加。ONOO- 负责蛋白质中酪氨酸残基的硝化；因此，血浆蛋白中硝基酪氨酸（NT）的存在被认为是ONOO- 生成的间接证据。已在糖尿病患者的血浆中发现NT，但在健康对照者的血浆中无法检测到。NT血浆值与血浆葡萄糖浓度相关，进一步探索急性高血糖对NT形成影响的研究证实，在高血糖钳夹期间的正常受试者以及高血糖灌注期间大鼠的工作心脏中都会产生NT。餐后高甘油三酯血症和高血糖被认为是心血管疾病的危险因素。有证据表明，餐后高甘油三酯血症和高血糖通过氧化应激诱导内皮功能障碍；然而，这两个因素的具体作用仍存在争议。在一项临床研究中，单独的高脂肪负荷和葡萄糖分别导致正常受试者和糖尿病患者的内皮功能下降和NT增加。当高脂肪负荷和葡萄糖联合使用时，这些影响更为明显。短期辛伐他汀治疗对血脂参数无影响，但减少了高脂肪负荷、单独葡萄糖以及高脂肪负荷和葡萄糖联合使用对内皮功能和NT的影响。长期辛伐他汀治疗伴随着餐后甘油三酯较小的升高，随后内皮功能和NT的变化也较小。这项研究表明餐后高甘油三酯血症和高血糖对内皮功能有独立的累积效应，提示氧化应激是这些效应的共同介导因素。辛伐他汀对氧化应激和内皮功能障碍显示出有益作用，这可能归因于药物的直接作用以及降脂作用。这些研究表明糖尿病中会生成ONOO-，提示ONOO- 可能参与糖尿病并发症的发生发展。
