Methylglyoxal impairs endothelial insulin sensitivity both in vitro and in vivo

Nigro, Cecilia; Raciti, Gregory Alexander; Leone, Arturo; Fleming, Thomas; Longo, Michele; Prevenzano, Immacolata; Fiory, Francesca; Mirra, Paola; D’Esposito, Vittoria; Ulianich, Luca; Nawroth, Peter P.; Formisano, Pietro; Béguinot, Francesco; Miele, Claudia

doi:10.1007/s00125-014-3243-7

Cited by 65 publications

(57 citation statements)

References 41 publications

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“…Consistent with eNOS activation, the insulin-induced NO release in the culture medium of MAECs was suppressed by 16 h MGO pre-treatment. Concomitant with this, the pre-treatment with MGO for 16 h significantly increased the ET-1 release in the culture medium of MAEC cells46. These experiments are in line with our observation regarding the methylglyoxal enrichment via GLO1-knockdown.…”

Section: Discussionsupporting

confidence: 91%

“…These results suggest that MGO regardless whether given extracellularly (MAEC-system) or accumulated by GLO1-knockdown (our model) causes an imbalance between NO and ET-1 production, which facilitates vasoconstriction. As discussed by Nigro et al ., NO may contribute to the activation of endothelin-converting enzyme-1 and the subsequent release of ET-146.…”

Section: Discussionmentioning

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: 91%

Section: Discussionmentioning

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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“…In addition to the effect of insulin on glucose metabolism, it also exerts a direct effect on endothelial cells. MGO has recently been identified as an inducer of endothelial insulin resistance [188]. It impairs the action of insulin on the endothelium both in vitro and in vivo, at least partly, through an ERK1/2-mediated mechanism.…”

Section: Insulin Resistancementioning

confidence: 99%

The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

2015

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The formation and accumulation of advanced glycation endproducts (AGEs) are related to diabetes and other age-related diseases. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is the major precursor in the formation of AGEs. MGO is mainly formed as a byproduct of glycolysis. Under physiological circumstances, MGO is detoxified by the glyoxalase system into D-lactate, with glyoxalase I (GLO1) as the key enzyme in the anti-glycation defence. New insights indicate that increased levels of MGO and the major MGO-derived AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1), and dysfunctioning of the glyoxalase system are linked to several age-related health problems, such as diabetes, cardiovascular disease, cancer and disorders of the central nervous system. The present review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system and its effect on biochemical pathways in relation to the development of age-related diseases. Although several scavengers of MGO have been developed over the years, therapies to treat MGO-associated complications are not yet available for application in clinical practice. Small bioactive inducers of GLO1 can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role.

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“…Suppression of DNA modification by MG and related mutation likely underlies the finding that Glo1 is a tumour suppressor gene [6]. Increased MG-H1 and related protein inactivation and dysfunction contributes to ageing [7], insulin resistance [8,9], cardiovascular disease [10], vascular complications of diabetes [4,11] and renal failure [12]. Increased MG concentration, a metabolic state called dicarbonyl stress, is driven by increased formation of MG and/or decreased activity of Glo1 [1].…”

Section: Introductionmentioning

confidence: 99%

“…If Glo1 expression had been decreased by 50% in heterozygote Glo1 mutant mice by successful gene trapping -as expected for functional knockout, a ca. 2-fold increased MG and consequent impaired metabolic, vascular and neurological health in the mutant mouse model is expected [8,[20][21][22]. In the IMKC project, the putative mutation of the Glo1 gene was assessed by measurement of Glo1 mRNA only.…”

Section: Introductionmentioning

confidence: 99%

Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cellsin vitro

Shafie

Xue

Barker

et al. 2016

Biochemical Journal

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Glyoxalase 1 (Glo1) is a cytoplasmic enzyme with a cytoprotective function linked to metabolism of the cytotoxic side product of glycolysis, methylglyoxal (MG). It prevents dicarbonyl stress — the abnormal accumulation of reactive dicarbonyl metabolites, increasing protein and DNA damage. Increased Glo1 expression delays ageing and suppresses carcinogenesis, insulin resistance, cardiovascular disease and vascular complications of diabetes and renal failure. Surprisingly, gene trapping by the International Mouse Knockout Consortium (IMKC) to generate putative Glo1 knockout mice produced a mouse line with the phenotype characterised as normal and healthy. Here, we show that gene trapping mutation was successful, but the presence of Glo1 gene duplication, probably in the embryonic stem cells (ESCs) before gene trapping, maintained wild-type levels of Glo1 expression and activity and sustained the healthy phenotype. In further investigation of the consequences of dicarbonyl stress in ESCs, we found that prolonged exposure of mouse ESCs in culture to high concentrations of MG and/or hypoxia led to low-level increase in Glo1 copy number. In clinical translation, we found a high prevalence of low-level GLO1 copy number increase in renal failure where there is severe dicarbonyl stress. In conclusion, the IMKC Glo1 mutant mouse is not deficient in Glo1 expression through duplication of the Glo1 wild-type allele. Dicarbonyl stress and/or hypoxia induces low-level copy number alternation in ESCs. Similar processes may drive rare GLO1 duplication in health and disease.

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Methylglyoxal impairs endothelial insulin sensitivity both in vitro and in vivo

Abstract: MGO impairs the action of insulin on the endothelium both in vitro and in vivo, at least in part through an ERK1/2-mediated mechanism. These findings may be instrumental in developing novel strategies for preserving endothelial function in diabetes.

Cited by 65 publications

References 41 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

The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cellsin vitro

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