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Date of Award
Background Endothelial dysfunction is one of the key figures in diabetes-related multi-organ damages, but the molecular mechanisms triggering endothelial dysfunction are not fully understood yet. Methylglyoxal (MGO), a highly reactive dicarbonyl mainly generated as a by-product of glycolysis, is increased in both type І and type ІІ diabetics. MGO can rapidly bind with proteins, nucleic acids and lipids, resulting in structural and functional changes of these targets and forming advanced glycation end products (AGEs). However, exactly how MGO renders endothelial cell dysfunction is not clear.
Methods and Results Human aortic endothelial cells (HAECs) from healthy (H-HAECs) and type ІІ diabetic (D-HAECs) donors were cultured in endothelial growth media (EGM-2). D-HAECs demonstrated impaired tube formation (on Matrigel) and proliferation (MTT assay), as well as increased apoptosis (caspase 3/7 activity assay), compared with H-HAECs. H-HAECs were treated with MGO (10µM) for 24 hours with or without ATP-sensitive potassium (KATP) channel antagonist glibenclamide (1µM). MGO (10µM) significantly impaired H-HAECs tube formation and proliferation, and induced cell apoptosis, all of which were reversed by glibenclamide. Meanwhile, activation of MAPK pathways p38 kinase, JNK, and ERK (determined by Western blot analyses of their phosphorylated forms, P-JNK, P-p38, and P-ERK) in D-HAECs were significantly enhanced compared with those in H-HAECs. MGO exposure enhanced the activation of all three MAPK pathways in H-HAECs, while glibenclamide reversed the activation of P-SAPK/JNK induced by MGO.
Conclusion Our data suggest that MGO triggers endothelial cell dysfunction by activating JNK/P38 MAPK pathway. Part of this effect is through activation of KATP channels. By understanding how MGO induces endothelial dysfunction, our study may provide useful information for developing MGO-targeted interventions to treat vascular disorders in diabetes.
Keywords: Diabetes; Endothelial cell; Methyglyoxal; Mitogen-activated protein kinases; ATP-sensitive potassium channel.
Wang, Yihan, "The Role Of Methylglyoxal In Endothelial Cell Dysfunction" (2018). Wayne State University Theses. 648.