Department of Internal Medicine, Division of General Internal Medicine, Laboratory for Metabolism and Vascular Medicine, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands.
J Biol Chem. 2011 Jan 14;286(2):1374-80. doi: 10.1074/jbc.M110.144097. Epub 2010 Nov 5.
The reactive advanced glycation end product (AGE) precursor methylglyoxal (MGO) and MGO-derived AGEs are associated with diabetic vascular complications and also with an increase in oxidative stress. Glyoxalase-I (GLO-I) transgenic rats were used to explore whether overexpression of this MGO detoxifying enzyme reduces levels of AGEs and oxidative stress in a rat model of diabetes. Rats were made diabetic with streptozotocin, and after 12 weeks, plasma and multiple tissues were isolated for analysis of AGEs, carbonyl stress, and oxidative stress. GLO-I activity was significantly elevated in multiple tissues of all transgenic rats compared with wild-type (WT) littermates. Streptozotocin treatment resulted in a 5-fold increase in blood glucose concentrations irrespective of GLO-I overexpression. Levels of MGO, glyoxal, 3-deoxyglucosone, AGEs, and oxidative stress markers nitrotyrosine, malondialdehyde, and F2-isoprostane were elevated in the diabetic WT rats. In diabetic GLO-I rats, glyoxal and MGO composite scores were significantly decreased by 81%, and plasma AGEs and oxidative stress markers scores were significantly decreased by ∼50%. Hyperglycemia induced a decrease in protein levels of the mitochondrial oxidative phosphorylation complex in the gastrocnemius muscle, which was accompanied by an increase in the lipid peroxidation product 4-hydroxy-2-nonenal, and this was counteracted by GLO-I overexpression. This study shows for the first time in an in vivo model of diabetes that GLO-I overexpression reduces hyperglycemia-induced levels of carbonyl stress, AGEs, and oxidative stress. The reduction of oxidative stress by GLO-I overexpression directly demonstrates the link between glycation and oxidative stress.
活性晚期糖基化终产物(AGE)前体甲基乙二醛(MGO)和 MGO 衍生的 AGEs 与糖尿病血管并发症有关,也与氧化应激增加有关。使用糖基化酶-I(GLO-I)转基因大鼠来探讨这种 MGO 解毒酶的过表达是否会降低糖尿病大鼠模型中 AGEs 和氧化应激的水平。大鼠用链脲佐菌素制成糖尿病,12 周后,分离血浆和多种组织用于分析 AGEs、羰基应激和氧化应激。与野生型(WT)同窝仔相比,所有转基因大鼠的多种组织中的 GLO-I 活性均显着升高。无论 GLO-I 是否过表达,链脲佐菌素处理都会导致血糖浓度增加 5 倍。MGO、乙二醛、3-脱氧葡萄糖酮、AGEs 和氧化应激标志物硝基酪氨酸、丙二醛和 F2-异前列腺素的水平在糖尿病 WT 大鼠中升高。在糖尿病 GLO-I 大鼠中,糖基化酶-I 过表达使复合评分中的乙二醛和 MGO 降低了 81%,并且使血浆 AGEs 和氧化应激标志物评分降低了约 50%。高血糖诱导比目鱼肌中线粒体氧化磷酸化复合物的蛋白质水平降低,同时脂质过氧化产物 4-羟基-2-壬烯醛增加,而过表达 GLO-I 可逆转这种情况。这项研究首次在糖尿病的体内模型中表明,GLO-I 过表达可降低高血糖诱导的羰基应激、AGEs 和氧化应激水平。GLO-I 过表达降低氧化应激直接证明了糖化和氧化应激之间的联系。