Methylglyoxal Causes Dysfunction of Thioredoxin and Thioredoxin Reductase in Endothelial Cells

Tatsunami, Ryosuke; Oba, Tatsuya; Takahashi, Kyohei; Tampo, Yoshiko

doi:10.1254/jphs.09131fp

Cited by 16 publications

(11 citation statements)

References 38 publications

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“…This suggests either that the Nrf2-dependent induction of Trx1 is impaired by MGO or that Trx1 is directly modified by MGO and targeted for degradation. In this regard, there is evidence that Trx1 can be inhibited, and expression of Trx1 decreased by MGO [27, 28], which seems to be controlled at the transcriptional level [29]. These observations combined with our data indicate that Trx1 is downregulated by MGO treatment in HT22 cells, a phenomenon not previously described for nerve cells.…”

Section: Discussionsupporting

confidence: 83%

“…The mitochondrial isoforms of Trx and TrxR presented the same expression pattern; however, they are underrepresented in the TrxR activity assay. The inhibition of purified Trx1 and TrxR1 by MGO has been described [27, 28] and this also seems to be the case in the HT22 cells treated with MGO. This hypothesis was further corroborated by TrxR1 immunoprecipitation studies, showing that TrxR1 is heavily glycated after MGO treatment, as compared to control cells where it presents no signs of glycation.…”

Section: Discussionmentioning

confidence: 82%

“…Similar to other proteins, Trx and TrxR have reactive cysteines that are among the most sensitive to oxidative stress [25, 26], and thus may be oxidized by reactive oxygen species or targeted by thiol-reacting molecules, such as MGO. There is some in vitro evidence that Trx [27] and TrxR [28] can be inhibited by MGO. Endothelial cells exposed to MGO present increased ROS production and typical signs of apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Methylglyoxal, the foe and friend of glyoxalase and Trx/TrxR systems in HT22 nerve cells

Dafre

Goldberg

Wang

et al. 2015

Free Radical Biology and Medicine

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Methylglyoxal (MGO) is a major glycating agent that reacts with basic residues of proteins and promotes the formation of advanced glycation end products (AGEs) which are believed to play key roles in a number of pathologies, such as diabetes, Alzheimer’s disease, and inflammation. Here, we examined the effects of MGO on immortalized mouse hippocampal HT22 nerve cells. The endpoints analyzed were MGO and thiol status, the glyoxalase system, comprising glyoxalase 1 and 2 (GLO1/2), and the cytosolic and mitochondrial Trx/TrxR systems, as well as nuclear Nrf2 and its target genes. We found that nuclear Nrf2 is induced by MGO treatment in HT22 cells, as corroborated by induction of the Nrf2-controlled target genes and proteins glutamate cysteine ligase and heme oxygenase 1. Nrf2 knockdown prevented MGO-dependent induction of glutamate cysteine ligase and heme oxygenase 1. The cystine/glutamate antiporter, system xc−, which is also controlled by Nrf2, was also induced. The increased cystine import (system xc−) activity and GCL expression promoted GSH synthesis, leading to increased levels of GSH. The data indicate that MGO can act as both a foe and a friend of the glyoxalase and the Trx/TrxR systems. At low concentrations of MGO (0.3 mM), GLO2 is strongly induced, but at high MGO (0.75 mM) concentrations, GLO1 is inhibited and GLO2 is downregulated. The cytosolic Trx/TrxR system is impaired by MGO, where Trx is downregulated yet TrxR is induced, but strong MGO-dependent glycation may explain the loss in TrxR activity. We propose that Nrf2 can be the unifying element to explain the observed upregulation of GSH, GCL, HO1, TrxR1, Trx2, TrxR2, and system xc− system activity.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Methylglyoxal, the foe and friend of glyoxalase and Trx/TrxR systems in HT22 nerve cells

Dafre

Goldberg

Wang

et al. 2015

Free Radical Biology and Medicine

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“…In the present study, we used relatively high but sublethal MGO (0.1 – 0.5 mM) concentrations, in a range broadly found in the literature [16,17,38], with the aim to demonstrate that Trx1 and Glo2 are molecular targets of MGO. Once such targets are identified, further studies with additional, relevant models are needed to further test the hypotheses.…”

Section: Discussionmentioning

confidence: 99%

“…Decreased levels of Trx in the neural tissue and increased levels in plasma and cerebrospinal fluid were found in Alzheimer disease patients, and such changes were correlated to clinical scores and were of prognostic value [14]. There is some in vitro evidence showing that components of the Trx/TrxR system are molecular targets of MGO toxicity [9,15,16]. Endothelial cells exposed to MGO downregulate Trx1 protein and mRNA copy number [17].…”

Section: Introductionmentioning

confidence: 99%

Methylglyoxal-induced AMPK activation leads to autophagic degradation of thioredoxin 1 and glyoxalase 2 in HT22 nerve cells

Dafre

Schmitz

Maher

2017

Free Radical Biology and Medicine

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Methylglyoxal (MGO) is a major glycating agent that reacts with basic residues of proteins and promotes the formation of advanced glycation end products which are believed to play key roles in a number of pathologies, such as diabetes, Alzheimer’s disease, and inflammation. We previously showed that MGO treatment targets the thioredoxin and the glyoxalase systems, leading to a decrease in Trx1 and Glo2 proteins in immortalized mouse hippocampal HT22 nerve cells. Here, we propose that autophagy is the underlying mechanism leading to Glo2 and Trx1 loss induced by MGO. The autophagic markers p62, and the lipidated and active form of LC3, were increased by MGO (0.5 mM). Autophagy inhibition with bafilomycin or chloroquine prevented the decrease in Trx1 and Glo2 at 6 and 18 h after MGO treatment. Proteasome inhibition by MG132 exacerbated the effect of MGO on Trx1 and Glo2 degradation (18 h), further suggesting a role for autophagy. ATG5 small interfering RNA protected Trx1 and Glo2 from MGO-induced degradation, confirming Trx1 and Glo2 loss is mediated by autophagy. In the search for the signals that control autophagy, we found that AMPK activation, a known autophagy inducer, was markedly increased by MGO treatment. AMPK activation was confirmed by increased acetyl coenzyme A carboxylase phosphorylation, a direct AMPK substrate and by decreased mTOR phosphorylation, an indirect marker of AMPK activation. To confirm that MGO-mediated Trx1 and Glo2 degradation was AMPK-dependent, AMPK-deficient mouse embryonic fibroblasts (MEFs) were treated with MGO. Wildtype MEFs presented the expected decrease in Trx1 and Glo2, while MGO was ineffective in decreasing these proteins in AMPK-deficient cells. Overall, the data indicate that MGO activates autophagy in an AMPK-dependent manner, and that autophagy was responsible for Trx1 and Glo2 degradation, confirming that Trx1 and Glo2 are molecular targets of MGO.

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The role of the thioredoxin/thioredoxin reductase system in the metabolic syndrome: towards a possible prognostic marker?

Tinkov

Bjørklund

Skalny

et al. 2018

Cell. Mol. Life Sci.

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Mammalian thioredoxin reductase (TrxR) is a selenoprotein with three existing isoenzymes (TrxR1, TrxR2, and TrxR3), which is found primarily intracellularly but also in extracellular fluids. The main substrate thioredoxin (Trx) is similarly found (as Trx1 and Trx2) in various intracellular compartments, in blood plasma, and is the cell's major disulfide reductase. Thioredoxin reductase is necessary as a NADPH-dependent reducing agent in biochemical reactions involving Trx. Genetic and environmental factors like selenium status influence the activity of TrxR. Research shows that the Trx/TrxR system plays a significant role in the physiology of the adipose tissue, in carbohydrate metabolism, insulin production and sensitivity, blood pressure regulation, inflammation, chemotactic activity of macrophages, and atherogenesis. Based on recent research, it has been reported that the modulation of the Trx/TrxR system may be considered as a new target in the management of the metabolic syndrome, insulin resistance, and type 2 diabetes, as well as in the treatment of hypertension and atherosclerosis. In this review evidence about a possible role of this system as a marker of the metabolic syndrome is reported.

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Methylglyoxal Causes Dysfunction of Thioredoxin and Thioredoxin Reductase in Endothelial Cells

Cited by 16 publications

References 38 publications

Methylglyoxal, the foe and friend of glyoxalase and Trx/TrxR systems in HT22 nerve cells

Methylglyoxal, the foe and friend of glyoxalase and Trx/TrxR systems in HT22 nerve cells

Methylglyoxal-induced AMPK activation leads to autophagic degradation of thioredoxin 1 and glyoxalase 2 in HT22 nerve cells

The role of the thioredoxin/thioredoxin reductase system in the metabolic syndrome: towards a possible prognostic marker?

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