Institute of Physiology, University of Coimbra, Portugal; IBILI, Faculty of Medicine, University of Coimbra, Portugal.
Pharmacol Res. 2012 May;65(5):497-506. doi: 10.1016/j.phrs.2012.03.004. Epub 2012 Mar 16.
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.
现代饮食可能导致现代疾病。研究已经将糖的代谢物甲基乙二醛 (MG) 与糖尿病并发症的发展联系起来，但确切的机制尚未完全阐明。本研究旨在研究 MG 是否可以直接影响 Wistar 和 Goto-Kakizaki (GK) 大鼠（2 型糖尿病动物模型）的内皮功能、氧化应激和炎症。用饮用水中 MG 处理 3 个月的 Wistar 和 GK 大鼠与各自的对照大鼠进行比较。研究了 MG 对来自不同组的大鼠离体主动脉中 NO 依赖性血管舒张的影响。还评估了胰岛素抵抗、NO 生物利用度、糖化、促炎生物标志物单核细胞趋化蛋白-1 (MCP-1) 和血管氧化应激。用 MG 处理的 Wistar 大鼠显著降低了 NO 依赖性血管舒张的功效（p<0.001）。这种损害伴随着氧化应激标志物硝基酪氨酸增加三倍。晚期糖基化终产物 (AGEs) 的形成也显著增加，MCP-1 和 AGEs 受体 (RAGE) 的表达也增加。NO 生物利用度显著降低，并伴有超氧化物阴离子免疫荧光增加。与对照 GK 大鼠相比，用 MG 处理的 GK 大鼠显著加重了内皮功能障碍、氧化应激、AGEs 积累和 NO 生物利用度降低。这些结果表明，MG 在正常 Wistar 大鼠中诱导内皮功能障碍，并加重 GK 大鼠中存在的内皮功能障碍。其机制至少部分是通过增加氧化应激和/或 AGEs 的形成，同时增加炎症和减少 NO 生物利用度。本研究进一步证明了甲基乙二醛是动脉粥样硬化发病机制和大血管糖尿病并发症发展的原因之一。
