Overexpression of glyoxalase-I reduces hyperglycemia-induced levels of advanced glycation end products and oxidative stress in diabetic rats.
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.
Department of Internal Medicine, Division of General Internal Medicine, Laboratory for Metabolism and Vascular Medicine, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands.
Olaf
O
Brouwers
Petra M
PM
Niessen
Isabel
I
Ferreira
Toshio
T
Miyata
Peter G
PG
Scheffer
Tom
T
Teerlink
Patrick
P
Schrauwen
Michael
M
Brownlee
Coen D
CD
Stehouwer
Casper G
CG
Schalkwijk
D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D017127:Glycation End Products, Advanced / Q000097:blood*; D006037:Glyoxal / Q000097:blood; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D007791:Lactoylglutathione Lyase / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000502:physiology*; D011247:Pregnancy; D011765:Pyruvaldehyde / Q000097:blood; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar
D015415:Biomarkers; D017127:Glycation End Products, Advanced; D006037:Glyoxal; D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase