Glycosylation with O-linked β-N-acetylglucosamine induces vascular dysfunction via production of superoxide anion/reactive oxygen species

Leonardo Souza-Silva, Rheure Alves-Lopes, Jéssica Silva Miguez, Vanessa Dela Justina, Karla Bianca Neves, Fabíola Leslie Mestriner, Rita de Cassia Tostes, Fernanda Regina Giachini, Victor Vitorino Lima

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Abstract

Overproduction of superoxide anion (•O2 ) and O-linked β-N-acetylglucosamine (O-GlcNAc) modification in the vascular system are contributors to endothelial dysfunction. This study tested the hypothesis that increased levels of O-GlcNAc-modified proteins contribute to •O2 production via activation of NADPH oxidase, resulting in impaired vasodilation. Rat aortic segments and vascular smooth muscle cells (VSMCs) were incubated with vehicle (methanol) or O-(2-acetamido-2-deoxy-d-glucopyranosylidenamino) N-phenylcarbamate (PUGNAc) (100 μM). PUGNAc produced a time-dependent increase in O-GlcNAc levels in VSMC and decreased endothelium-dependent relaxation, which was prevented by apocynin and tiron, suggesting that •O2 contributes to endothelial dysfunction under augmented O-GlcNAc levels. Aortic segments incubated with PUGNAc also exhibited increased levels of reactive oxygen species, assessed by dihydroethidium fluorescence, and augmented •O2 production, determined by lucigenin-enhanced chemiluminescence. Additionally, PUGNAc treatment increased Nox-1 and Nox-4 protein expression in aortas and VSMCs. Translocation of the p47phox subunit from the cytosol to the membrane was greater in aortas incubated with PUGNAc. VSMCs displayed increased p22phox protein expression after PUGNAc incubation, suggesting that NADPH oxidase is activated in conditions where O-GlcNAc protein levels are increased. In conclusion, O-GlcNAc levels reduce endothelium-dependent relaxation by overproduction of •O2 via activation of NADPH oxidase. This may represent an additional mechanism by which augmented O-GlcNAc levels impair vascular function.

Original languageEnglish
Pages (from-to)232-240
Number of pages9
JournalCanadian Journal of Physiology and Pharmacology
Volume96
Issue number3
Early online date9 Aug 2017
DOIs
Publication statusPublished - 1 Mar 2018

Keywords

  • oxidative stress
  • post-translational modification
  • PUGNAc
  • vascular reactivity
  • vasodilation

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