Overexpression of Glyoxalase-I Reduces Hyperglycemia-induced Levels of Advanced Glycation End Products and Oxidative Stress in Diabetic Rats.

O. Brouwers, P.M. Niessen, I. Ferreira, T. Miyata, P.G. Scheffer, T. Teerlink, P. Schrauwen, M. Brownlee, C.D.A. Stehouwer, C.G. Schalkwijk

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Abstract

The reactive advanced glycation endproduct (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 fivefold increase in blood glucose concentrations irrespective of GLO-I overexpression. Levels of MGO, glyoxal (GO), 3-deoxyglucosone, AGEs and oxidative stress markers nitrotyrosine, malondialdehyde and F2-isoprostane were elevated in the diabetic WT rats. In diabetic GLO-I rats, GO and MGO composite scores were significantly decreased by 81%, and plasma AGEs and oxidative stress markers scores by approximately 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.
Original languageEnglish
Pages (from-to)1374-1380
JournalJournal of Biological Chemistry
Volume286
Issue number2
DOIs
Publication statusPublished - 1 Jan 2011

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