Methylglyoxal promotes oxidative stress and endothelial dysfunction
Graphical abstract
Introduction
Methylglyoxal (MG) is a highly reactive electrophilic α,β-dicarbonyl aldehyde compound formed mainly during glycolysis [1], [2], [3]. The 1,2-dicarbonyl compounds, including MG, glyoxal and 3-deoxyglucosone, are generated either endogenously by cell metabolism, glucose oxidation and lipid peroxidation or by degradation of carbohydrates in foods and beverages. Highly reactive dicarbonyls attack the lysine, arginine and cysteine residues of long-lived proteins, such as collagens, to form irreversible AGEs [4]. An excess of MG formation can increase ROS production and cause oxidative stress. MG reacts with proteins, DNA and other biomolecules, and is a major precursor of advanced glycation end products (AGEs). AGEs are also associated with the aging process and age-related diseases such as cardiovascular complications of diabetes, neurodegenerative diseases and connective tissue disorders.
Under physiological conditions, the glyoxalase system degrades MG into d-lactate with the help of reduced glutathione [2], [5] and keeps plasma MG levels low. Hyperglycemia associated with diabetes drives several damage pathways and raises concentrations of the reactive dicarbonyl, MG. Since plasma MG levels are elevated two- to fourfold in diabetic patients [5], [6], MG is involved in diabetes-associated vascular endothelial damage, which may lead to atherosclerosis. Increased MG-derived AGEs level in diabetic patients seems to correlate with diabetic complications [7], [8]. Moreover, it has been recently shown that exposure of mesenteric arteries to MG, in vitro, leads to impaired endothelium-dependent vasorelaxation [9]. Furthermore, it was also described that oral administration of MG increased blood pressure in Wistar–Kyoto rats [10]. Therefore it is feasible that chronic treatment with MG may directly affect vascular function. Thus, we hypothesize that over-consumption of MG could contribute to the development of endothelial dysfunction. The current study investigates the effect of chronic MG treatment on endothelial function, oxidative stress, inflammation and AGEs formation in Wistar and GK diabetic rats.
Section snippets
Drugs
Methylglyoxal, phenylephrine, acetylcholine, NG-nitro-l-arginine-methyl ester (l-NAME), and polyethylene glycol-superoxide dismutase were obtained from SIGMA (St. Louis, MO, USA). Anti-Nɛ-carboxyethyl-lysine (CEL), total AGEs (6D12), vasodilator-stimulated phosphoprotein (VASP), pVASP, and nitrotyrosine were obtained from Trans Genic Inc. (Tokyo, Japan), Cell Signaling Technology (Danvers, MA, USA) and Upstate Biotechnology (Lake placid, NY, USA), respectively. Anti- MCP-1 and β-actin, were
Metabolic parameters
Glycemia and plasma concentrations of MG, free fatty acids, and total cholesterol levels were elevated in GK rats when compared to their corresponding control Wistar values (Table 1, Table 2). In agreement with the increase in kidney weight, urine analysis revealed albuminuria in this model of type 2 diabetes (Table 1). Methylglyoxal (MG) treatment for three months in W rats (W+MG) significantly increased plasma MG levels, free fatty acids and urinary albumin excretion (UAE) while no changes
Discussion
The present study shows for the first time that exogenous administration of methylglyoxal leads to endothelial dysfunction in normal Wistar rats and aggravates the endothelial impairment of diabetic GK rats. Aortic oxidative stress, inflammation and AGEs levels are increased and related to impaired NO bioavailability (pVASP). This is consistent with the demonstration that incubation of mesenteric arteries with methylglyoxal, in vitro, leads to impaired endothelium-dependent vasorelaxation in a
Conflict of interest
The authors report no conflict of interest.
Acknowledgments
We wish to thank Ilda da Conceição (Department of Pathological Anatomy, University Hospitals of Coimbra) for her technical assistance in histological preparations. The present work was supported by FCT, projects PTDC/SAU-MET/115635/2009 and Pest-C/SAU/UI3282/2011.
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