title: Methylglyoxal promotes oxidative stress and endothelial dysfunction.
abstract: Modern diets can cause modern diseases. Research has linked a metabolite of sugar, methylglyoxal (MG), to the development of diabetic complications, but the exact mechanism has not been fully elucidated. The present study was designed to investigate whether MG could directly influence endothelial function, oxidative stress and inflammation in Wistar and Goto-Kakizaki (GK) rats, an animal model of type 2 diabetes. Wistar and GK rats treated with MG in the drinking water for 3 months were compared with the respective control rats. The effects of MG were investigated on NO-dependent vasorelaxation in isolated rat aortic arteries from the different groups. Insulin resistance, NO bioavailability, glycation, a pro-inflammatory biomarker monocyte chemoattractant protein-1 (MCP-1) and vascular oxidative stress were also evaluated. Methylglyoxal treated Wistar rats significantly reduced the efficacy of NO-dependent vasorelaxation (p<0.001). This impairment was accompanied by a three fold increase in the oxidative stress marker nitrotyrosine. Advanced glycation endproducts (AGEs) formation was significantly increased as well as MCP-1 and the expression of the receptor for AGEs (RAGE). NO bioavailability was significantly attenuated and accompanied by an increase in superoxide anion immunofluorescence. Methylglyoxal treated GK rats significantly aggravated endothelial dysfunction, oxidative stress, AGEs accumulation and diminished NO bioavailability when compared with control GK rats. These results indicate that methylglyoxal induced endothelial dysfunction in normal Wistar rats and aggravated the endothelial dysfunction present in GK rats. The mechanism is at least in part by increasing oxidative stress and/or AGEs formation with a concomitant increment of inflammation and a decrement in NO bioavailability. The present study provides further evidence for methylglyoxal as one of the causative factors in the pathogenesis of atherosclerosis and development of macrovascular diabetic complication.
authors.affiliation: Institute of Physiology, University of Coimbra, Portugal; IBILI, Faculty of Medicine, University of Coimbra, Portugal. csena@ci.uc.pt
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Sena
authors.forename: Paulo
authors.initials: P
authors.lastname: Matafome
authors.forename: Joana
authors.initials: J
authors.lastname: Crisóstomo
authors.forename: Lisa
authors.initials: L
authors.lastname: Rodrigues
authors.forename: Rosa
authors.initials: R
authors.lastname: Fernandes
authors.forename: Paulo
authors.initials: P
authors.lastname: Pereira
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Seiça
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D017127:Glycation End Products, Advanced; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; D011765:Pyruvaldehyde