Overexpression of Glyoxalase-I Reduces Hyperglycemia-induced Levels of Advanced Glycation End Products and Oxidative Stress in Diabetic Rats
Overexpression of Glyoxalase-I Reduces Hyperglycemia-induced Levels of Advanced Glycation End Products and Oxidative Stress in Diabetic Rats
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DOI：
10.1074/jbc.m110.144097
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发表时间：
2011-01-14
影响因子：
4.8
通讯作者：
Schalkwijk, Casper G.
中科院分区：
文献类型：
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作者：
Brouwers, Olaf;Niessen, Petra M.;Schalkwijk, Casper G.
反应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和氧化应激增加有关。采用GLO-I转基因大鼠，探讨过表达这种MGO解毒酶是否会降低糖尿病大鼠模型中的AGEs和氧化应激水平。用链脲佐菌素致糖尿病大鼠，12周后分离血浆和多个组织进行AGEs、羰基应激和氧化应激分析。与野生型（WT）仔鼠相比，所有转基因大鼠的多个组织中glo - 1活性显著升高。链脲佐菌素治疗导致血糖浓度升高5倍，与gloi过表达无关。糖尿病WT大鼠的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 -异前列腺素水平升高。在糖尿病glo - 1大鼠中，乙二醛和MGO复合评分显著降低81%，血浆AGEs和氧化应激标志物评分显著降低50%。高血糖导致腓肠肌线粒体氧化磷酸化复合物蛋白水平下降，同时脂质过氧化产物4-羟基-2-壬烯醛增加，这被gloi过表达抵消。该研究首次在体内糖尿病模型中表明，gloi过表达可降低高血糖诱导的羰基应激、AGEs和氧化应激水平。gloi过表达对氧化应激的降低直接证明了糖基化与氧化应激之间的联系。
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 similar to 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.