Buthionine Sulfoximine Promotes Methylglyoxal-Induced Apoptotic Cell Death and Oxidative Stress in Endothelial Cells

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

doi:10.1248/bpb.33.556

Cited by 23 publications

(11 citation statements)

References 36 publications

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“…The loss of EC number and function in diabetes is well described ( 31 ) and largely occurs due to the accumulation of MG ( 32 , 33 ). In our study, the detrimental effect of hyperglycemia on ECs was evident: the number of vWF + and CD31 + ECs was reduced in the hearts of WT-diabetic mice, and neuregulin and eNOS expression was reduced.…”

Section: Discussionmentioning

confidence: 99%

Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the Development of Diabetic Cardiomyopathy

et al. 2016

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The mechanisms for the development of diabetic cardiomyopathy remain largely unknown. Methylglyoxal (MG) can accumulate and promote inflammation and vascular damage in diabetes. We examined if overexpression of the MG-metabolizing enzyme glyoxalase 1 (GLO1) in macrophages and the vasculature could reduce MG-induced inflammation and prevent ventricular dysfunction in diabetes. Hyperglycemia increased circulating inflammatory markers in wild-type (WT) but not in GLO1-overexpressing mice. Endothelial cell number was reduced in WT-diabetic hearts compared with nondiabetic controls, whereas GLO1 overexpression preserved capillary density. Neuregulin production, endothelial nitric oxide synthase dimerization, and Bcl-2 expression in endothelial cells was maintained in the hearts of GLO1-diabetic mice and corresponded to less myocardial cell death compared with the WT-diabetic group. Lower receptor for advanced glycation end products and tumor necrosis factor-α (TNF-α) levels were also observed in GLO1-diabetic versus WT-diabetic mice. Over a period of 8 weeks of hyperglycemia, GLO1 overexpression delayed and limited the loss of cardiac function. In vitro, MG and TNF-α were shown to synergize in promoting endothelial cell death, which was associated with increased angiopoietin 2 expression and reduced Bcl-2 expression. These results suggest that MG in diabetes increases inflammation, leading to endothelial cell loss. This contributes to the development of diabetic cardiomyopathy and identifies MG-induced endothelial inflammation as a target for therapy.

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Section: Discussionmentioning

confidence: 99%

Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the Development of Diabetic Cardiomyopathy

et al. 2016

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“…Other studies have shown that MGO impairs HIF-1α degradation and signaling 19,20 and activates AMPK mediated autophagic degradation of thioredoxin 1 21 , thus emphasizing its influence on redox homeostasis 22 . Despite the clear association between reactive carbonyl species and diabetic complications, their mode of action on endothelial cells is discussed ambiguously 23–27 . A general finding throughout all studies is however that MGO causes endothelial damage, albeit that different MGO concentrations have been reported at which this occurs 23,28–30 .…”

Section: Introductionmentioning

confidence: 99%

Methylglyoxal down-regulates the expression of cell cycle associated genes and activates the p53 pathway in human umbilical vein endothelial cells

Braun

Pastene

Breedijk

et al. 2019

Sci Rep

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Although methylglyoxal (MGO) has emerged as key mediator of diabetic microvascular complications, the influence of MGO on the vascular transcriptome has not thoroughly been assessed. Since diabetes is associated with low grade inflammation causing sustained nuclear factor-kappa B (NF-κB) activation, the current study addressed 1) to what extent MGO changes the transcriptome of human umbilical vein endothelial cells (HUVECs) exposed to an inflammatory milieu, 2) what are the dominant pathways by which these changes occur and 3) to what extent is this affected by carnosine, a putative scavenger of MGO. Microarray analysis revealed that exposure of HUVECs to high MGO concentrations significantly changes gene expression, characterized by prominent down-regulation of cell cycle associated genes and up-regulation of heme oxygenase-1 (HO-1). KEGG-based pathway analysis identified six significantly enriched pathways of which the p53 pathway was the most affected. No significant enrichment of inflammatory pathways was found, yet, MGO did inhibit VCAM-1 expression in Western blot analysis. Carnosine significantly counteracted MGO-mediated changes in a subset of differentially expressed genes. Collectively, our results suggest that MGO initiates distinct transcriptional changes in cell cycle/apoptosis genes, which may explain MGO toxicity at high concentrations. MGO did not augment TNF-α induced inflammation.

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“…GSH is reported to have a protective effect against brain vascular endothelial dysfunction, including endothelial barrier permeability [ 19 ], cell death [ 20 ], and the scavenging of ROS [ 21 ]. GSH depletion elicits endothelial oxidative stress and cell apoptosis [ 20 , 22 ]. Some clinical studies demonstrate that an increased risk for stroke is associated with low levels of GSH in the brain [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Glutathione Suppresses Cerebral Infarct Volume and Cell Death after Ischemic Injury: Involvement of FOXO3 Inactivation and Bcl2 Expression

Song

Park

et al. 2015

Oxidative Medicine and Cellular Longevity

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Ischemic stroke interrupts the flow of blood to the brain and subsequently results in cerebral infarction and neuronal cell death, leading to severe pathophysiology. Glutathione (GSH) is an antioxidant with cellular protective functions, including reactive oxygen species (ROS) scavenging in the brain. In addition, GSH is involved in various cellular survival pathways in response to oxidative stress. In the present study, we examined whether GSH reduces cerebral infarct size after middle cerebral artery occlusion in vivo and the signaling mechanisms involved in the promotion of cell survival after GSH treatment under ischemia/reperfusion conditions in vitro. To determine whether GSH reduces the extent of cerebral infarction, cell death after ischemia, and reperfusion injury, we measured infarct size in ischemic brain tissue and the expression of claudin-5 associated with brain infarct formation. We also examined activation of the PI3K/Akt pathway, inactivation of FOXO3, and expression of Bcl2 to assess the role of GSH in promoting cell survival in response to ischemic injury. Based on our results, we suggest that GSH might improve the pathogenesis of ischemic stroke by attenuating cerebral infarction and cell death.

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Buthionine Sulfoximine Promotes Methylglyoxal-Induced Apoptotic Cell Death and Oxidative Stress in Endothelial Cells

Cited by 23 publications

References 36 publications

Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the Development of Diabetic Cardiomyopathy

Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the Development of Diabetic Cardiomyopathy

Methylglyoxal down-regulates the expression of cell cycle associated genes and activates the p53 pathway in human umbilical vein endothelial cells

Glutathione Suppresses Cerebral Infarct Volume and Cell Death after Ischemic Injury: Involvement of FOXO3 Inactivation and Bcl2 Expression

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