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Methylglyoxal-Induced Dysfunction in Brain Endothelial Cells via the Suppression of Akt/HIF-1α Pathway and Activation of Mitophagy Associated with Increased Reactive Oxygen Species

College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea
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Author to whom correspondence should be addressed.
These authors contributed equally to this study.
Antioxidants 2020, 9(9), 820; https://doi.org/10.3390/antiox9090820
Received: 9 July 2020 / Revised: 20 August 2020 / Accepted: 1 September 2020 / Published: 3 September 2020
(This article belongs to the Special Issue Redox Biology of Glyoxalases )
Methylglyoxal (MG) is a dicarbonyl compound, the level of which is increased in the blood of diabetes patients. MG is reported to be involved in the development of cerebrovascular complications in diabetes, but the exact mechanisms need to be elucidated. Here, we investigated the possible roles of oxidative stress and mitophagy in MG-induced functional damage in brain endothelial cells (ECs). Treatment of MG significantly altered metabolic stress as observed by the oxygen-consumption rate and barrier-integrity as found in impaired trans-endothelial electrical resistance in brain ECs. The accumulation of MG adducts and the disturbance of the glyoxalase system, which are major detoxification enzymes of MG, occurred concurrently. Reactive oxygen species (ROS)-triggered oxidative damage was observed with increased mitochondrial ROS production and the suppressed Akt/hypoxia-inducible factor 1 alpha (HIF-1α) pathway. Along with the disturbance of mitochondrial bioenergetic function, parkin-1-mediated mitophagy was increased by MG. Treatment of N-acetyl cysteine significantly reversed mitochondrial damage and mitophagy. Notably, MG induced dysregulation of tight junction proteins including occludin, claudin-5, and zonula occluden-1 in brain ECs. Here, we propose that diabetic metabolite MG-associated oxidative stress may contribute to mitochondrial damage and autophagy in brain ECs, resulting in the dysregulation of tight junction proteins and the impairment of permeability. View Full-Text
Keywords: methylglyoxal; hypoxia-inducible factor 1 (HIF-1α); mitophagy; oxidative stress; brain endothelial cells methylglyoxal; hypoxia-inducible factor 1 (HIF-1α); mitophagy; oxidative stress; brain endothelial cells
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MDPI and ACS Style

Kim, D.; Kim, K.-A; Kim, J.-H.; Kim, E.-H.; Bae, O.-N. Methylglyoxal-Induced Dysfunction in Brain Endothelial Cells via the Suppression of Akt/HIF-1α Pathway and Activation of Mitophagy Associated with Increased Reactive Oxygen Species. Antioxidants 2020, 9, 820. https://doi.org/10.3390/antiox9090820

AMA Style

Kim D, Kim K-A, Kim J-H, Kim E-H, Bae O-N. Methylglyoxal-Induced Dysfunction in Brain Endothelial Cells via the Suppression of Akt/HIF-1α Pathway and Activation of Mitophagy Associated with Increased Reactive Oxygen Species. Antioxidants. 2020; 9(9):820. https://doi.org/10.3390/antiox9090820

Chicago/Turabian Style

Kim, Donghyun; Kim, Kyeong-A; Kim, Jeong-Hyeon; Kim, Eun-Hye; Bae, Ok-Nam. 2020. "Methylglyoxal-Induced Dysfunction in Brain Endothelial Cells via the Suppression of Akt/HIF-1α Pathway and Activation of Mitophagy Associated with Increased Reactive Oxygen Species" Antioxidants 9, no. 9: 820. https://doi.org/10.3390/antiox9090820

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