<i>Reversal of Hyperglycemia‐Induced Angiogenesis Deficit of Human Endothelial Cells by Overexpression of Glyoxalase 1</i><scp>In Vitro</scp>

Ahmed, Usman; Dobler, Darin; Larkin, Sarah J.; Rabbani, Naila; Thornalley, Paul J.

doi:10.1196/annals.1433.035

Cited by 44 publications

(41 citation statements)

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“…The increase in MG found in our study was of similar level achieved with the GLO1 inhibitor BBGD that increased EC anoikis15 and was prevented by overexpression of GLO116. Similar proportionate increases in the MG concentration of culture medium are expected as MG permeates cell membranes with a half-life of <15 min23.…”

Section: Discussionsupporting

confidence: 84%

“…Increased MG concentration in cells and culture medium leads to increased formation of MG-H1 in integrin binding sites of collagen type-IV, resulting in endothelial cell detachment and anoikis15. Increased glycation of cellular proteins is likely linked to increased formation of ROS and inflammatory signalling1416. Conversely, inhibition of GLO1 with a specific GLO1 inhibitor, S-p-bromobenzylglutathione cyclopentyl diester (BBGSHCp 2 ) led to accumulation of MG in low glucose concentration and dysfunction similar to that found in the hyperglycaemia model15.…”

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confidence: 99%

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Glyoxalase 1-knockdown in human aortic endothelial cells – effect on the proteome and endothelial function estimates

Stratmann

Engelbrecht

Espelage

et al. 2016

Sci Rep

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Methylglyoxal (MG), an arginine-directed glycating agent, is implicated in diabetic late complications. MG is detoxified by glyoxalase 1 (GLO1) of the cytosolic glyoxalase system. The aim was to investigate the effects of MG accumulation by GLO1-knockdown under hyperglycaemic conditions in human aortic endothelial cells (HAECs) hypothesizing that the accumulation of MG accounts for the deleterious effects on vascular function. SiRNA-mediated knockdown of GLO1 was performed and MG concentrations were determined. The impact of MG on the cell proteome and targets of MG glycation was analysed, and confirmed by Western blotting. Markers of endothelial function and apoptosis were assessed. Collagen content was assayed in cell culture supernatant. GLO1-knockdown increased MG concentration in cells and culture medium. This was associated with a differential abundance of cytoskeleton stabilisation proteins, intermediate filaments and proteins involved in posttranslational modification of collagen. An increase in fibrillar collagens 1 and 5 was detected. The extracellular concentration of endothelin-1 was increased following GLO1-knockdown, whereas the phosphorylation and amount of eNOS was not influenced by GLO1-knockdown. The expression of ICAM-1, VCAM-1 and of MCP-1 was elevated and apoptosis was increased. MG accumulation by GLO1-knockdown provoked collagen expression, endothelial inflammation and dysfunction and apoptosis which might contribute to vascular damage.

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Section: Discussionsupporting

confidence: 84%

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confidence: 99%

Glyoxalase 1-knockdown in human aortic endothelial cells – effect on the proteome and endothelial function estimates

Stratmann

Engelbrecht

Espelage

et al. 2016

Sci Rep

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“…Experimental evidence is currently best established for vascular complications of diabetes. In cell culture systems incubated in high glucose concentrations to model diabetes associated hyperglycemia, overexpression of Glo1 prevented increased formation of ROS, inflammatory mediators S100A8, S100A12 and high mobility box-1 protein, and increased expression of the receptor for advanced glycation endproducts (RAGE) [47], and corrected decreased angiogenesis of endothelial cells [48] and dysfunction of endothelial progenitor cells [49]. Employing Glo1 transgenic rats, overexpression of Glo1 in vivo decreased the AGE and oxidative damage marker contents of tissues and prevented impairment of endothelium-dependent vasorelaxation of the streptozotocin-induced diabetic rats [37;50].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation

Xue

Rabbani

Momiji

et al. 2012

Biochemical Journal

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Word count: 5056. 2 SYNOPSISAbnormal cellular accumulation of the dicarbonyl metabolite methylglyoxal occurs on exposure to high glucose concentration, inflammation, cell ageing and senescence. It is associated with increased methylglyoxal-adduct content of protein and DNA linked to increased DNA strand breaks and mutagenesis, mitochondrial dysfunction and reactive oxygen species formation and cell detachment from the extracellular matrix. Methylglyoxalmediated damage is countered by glutathione-dependent metabolism by glyoxalase-1. It is not known, however, if glyoxalase-1 has stress responsive up-regulation to counter periods of high methylglyoxal concentration or dicarbonyl stress. We identified a functional antioxidant response element in the 5'-untranslated region of exon-1 of the mammalian glyoxalase-1 gene. Transcription factor Nrf2 binds to this antioxidant response element increasing basal and inducible expression of glyoxalase 1. Activators of Nrf2 induced increased glyoxalase-1 mRNA, protein and activity. Increased expression of glyoxalase-1 decreased cellular and extracellular concentrations of methylglyoxal, methylglyoxal -derived protein adducts, mutagenesis and cell detachment. Hepatic, brain, heart, kidney and lung glyoxalase-1 mRNA and protein were decreased in Nrf2 (-/-) mice and urinary excretion of methylglyoxal protein and nucleotide adducts were increased ca. 2-fold. We conclude that dicarbonyl stress is countered by up-regulation of glyoxalase-1 in the Nrf2 stress responsive system, protecting protein and DNA from increased damage and preserving cell function.Key words: Nrf2, glyoxalase, methylglyoxal, DNA damage, protein damage, glycation.Abbreviations used: AITC, allyl isothiocyanate; ARE, antioxidant response element; CDDOMe, methyl 2-cyano-3,12-dioxo-oleana-1,9(11)dien-28-oate; ChIP, chromatin immunoprecipitation; CNC, cap 'n' collar; ECL, enhanced chemiluminescence; Glo1, glyoxalase 1; keap1, kelch (β-propeller tertiary structure)-like erythroid cell-derived protein with CNC homology-associated protein 1; IRE, insulin response element; MG, methylglyoxal; MGdG, 3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purin-9(8)one; MG-H1, N  -(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine; Nrf2, nuclear erythroid factor E2 related factor-2; ROS, reactive oxygen species; SFN, sulforaphane; TBST, tris-buffered saline with Tween-20. 3 INTRODUCTIONModification of proteins and DNA by the dicarbonyl metabolite methylglyoxal (MG) has emerged as an important endogenous threat to the functional integrity of the proteome and genome. MG is formed by the spontaneous degradation of triosephosphate intermediates and is an unavoidable by-product of anaerobic glycolysis [1]. MG reacts with proteins and DNA forming quantitatively major adducts of endogenous damage, similar to and in some cases exceeding the steady-state levels of adducts produced by oxidative damage. Modification of proteins by MG is directed to arginine residues forming the hydroimidazolone, N  -(5-hydro-5-methyl-4-imi...

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“…A fraction of GSH is present as S-nitroso-GSH, a transnitrosylating agent generated from nitric oxide or its metabolites (168). 4) GSH functions in metabolism as a coenzyme for formaldehyde dehydrogenase, glyoxylase, and other metabolic reactions (4,168). In these reactions, GSH is cyclically removed by one reaction and regenerated in a second reaction.…”

Section: Gsh and Trxs As Common Control Nodes For Protein Thiol Redoxmentioning

confidence: 99%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

1,020

839

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Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the "redox hypothesis," is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to twoelectron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-B), receptor activation (e.g., ␣IIb␤3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.thioredoxin; glutathione; cysteine; hydrogen peroxide; redox signaling; protein thiol ONE OF THE GREAT REDOX BIOLOGISTS of the past century, Howard S. Mason, professed that to advance science, a scientist must interpret observations at the limit of their meaning. The present review of the redox biology of thiol systems addresses the possibility that disruption of the function and homeostasis of thiol systems is the most central feature of oxidative stress that contributes to mechanisms of aging and age-related disease. I have termed this the "redox hypothesis" to facilitate distinction from free radical hypotheses.Many proteins contain redox-sensitive thiols, and reactions of thiol systems occur largely by nonradical two-electron transfers. Accumulating data show that central thiol-disulfide couples are maintained under nonequilibrium conditions in biological systems. This presents a condition wherein changes in abundance and distribution of redox catalysts and changes in rates of generation of relevant oxidants (e.g., peroxides) and precursors for NADPH supply can account for pathological effects of oxidative stress through altered functions of enzymes, receptors, transporters, transcription factors, and structural elements, without free ra...

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Reversal of Hyperglycemia‐Induced Angiogenesis Deficit of Human Endothelial Cells by Overexpression of Glyoxalase 1In Vitro

Cited by 44 publications

References 20 publications

Glyoxalase 1-knockdown in human aortic endothelial cells – effect on the proteome and endothelial function estimates

Glyoxalase 1-knockdown in human aortic endothelial cells – effect on the proteome and endothelial function estimates

Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation

Radical-free biology of oxidative stress

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