Dicarbonyls induce senescence of human vascular endothelial cells

Santos, Anne Navarrete; Jacobs, Kathleen; Simm, Andreas; Glaubitz, Nicole; Horstkorte, Rüdiger; Hofmann, Britt

doi:10.1016/j.mad.2017.07.009

Cited by 21 publications

(8 citation statements)

References 32 publications

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“…The mechanism of glucose-induced senescence is not clear, although potential candidates include mitochondrial dysfunction, oxidative and glycosative cellular stress, decreased Nitric Oxide (NO) bioavailability, and molecular pathways leading to the activation of P53-driven DNA damage responses. 10,[13][14][15][16][17][18][19][20] We previously demonstrated in vitro the potential atherogenic changes in HUVECs earlier exposed to the specific metabolic milieu of gestational diabetes, proving that endothelial cells exposed in vivo even transiently to hyperglycaemia, oxidative stress and inflammation exhibit durable pro-atherogenic modifications. 13 More recently, we demonstrated that in cultured HUVECs the cytotoxic effect of elevated glucose levels was associated with oxidative and glycosative cellular stress, increased glutathione oxidized/ glutathione reduced (GSSG/GSH) ratio, and strong reduction in the catalase/superoxide dismutase (CAT/SOD) ratio, which is suggestive of an impairment of the superoxide anion/ hydrogen peroxide (O • − 2 /H 2 O 2 ) detoxification process.…”

Section: Introductionmentioning

confidence: 92%

“…Likewise, numerous in vitro studies demonstrated that elevated glucose levels increase the senescence and/or apoptosis both in endothelial cells and endothelial progenitor cells (EPCs). The mechanism of glucose‐induced senescence is not clear, although potential candidates include mitochondrial dysfunction, oxidative and glycosative cellular stress, decreased Nitric Oxide (NO) bioavailability, and molecular pathways leading to the activation of P53‐driven DNA damage responses 10,13‐20 …”

Section: Introductionmentioning

confidence: 99%

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Endothelial cells from umbilical cord of women affected by gestational diabetes: A suitable in vitro model to study mechanisms of early vascular senescence in diabetes

et al. 2021

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Human umbilical cord endothelial cells (HUVECs) obtained from women affected by gestational diabetes (GD‐HUVECs) display durable pro‐atherogenic modifications and might be considered a valid in vitro model for studying chronic hyperglycemia effects on early endothelial senescence. Here, we demonstrated that GD‐ compared to C‐HUVECs (controls) exhibited oxidative stress, altered both mitochondrial membrane potential and antioxidant response, significant increase of senescent cells characterized by a reduced NAD‐dependent deacetylase sirtuin‐1 (SIRT1) activity together with an increase in cyclin‐dependent kinase inhibitor‐2A (P16), cyclin‐dependent kinase inhibitor‐1 (P21), and tumor protein p53 (P53) acetylation. This was associated with the p300 activation, and its silencing significantly reduced the GD‐HUVECs increased protein levels of P300 and Ac‐P53 thus indicating a persistent endothelial senescence via SIRT1/P300/P53/P21 pathway. Overall, our data suggest that GD‐HUVECs can represent an “endothelial hyperglycemic memory” model to investigate in vitro the early endothelium senescence in cells chronically exposed to hyperglycemia in vivo.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Endothelial cells from umbilical cord of women affected by gestational diabetes: A suitable in vitro model to study mechanisms of early vascular senescence in diabetes

et al. 2021

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“…In addition to impaired formation of NO, increased oxidative stress is also involved in endothelial function in diabetes. The addition of high concentrations of MGO to endothelial cells induces oxidative stress by stimulating superoxide production (100,385,399), but also causes genotoxicity (240,270) and apoptosis (101,151,405,420). However, it should be emphasized that in most of these in vitro studies, high and nonphysiological concentrations of MGO were derived from commercial stock solutions, which are often contaminated with formaldehyde and other substances (455).…”

Section: A Methylglyoxal and Endothelial Dysfunction In Diabetesmentioning

confidence: 99%

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

Schalkwijk

Stehouwer

2020

Physiological Reviews

391

330

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The formation and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl compound, has been implicated in the pathogenesis of type 2 diabetes, vascular complications of diabetes, and several other age-related chronic inflammatory diseases such as cardiovascular disease, cancer and disorders of the central nervous system. MGO is mainly formed as a byproduct of glycolysis and, under physiological circumstances, detoxified by the glyoxalase system. MGO is the major precursor of non-enzymatic glycation of proteins and DNA, subsequently leading to the formation of advanced glycation endproducts (AGEs). MGO and MGO-derived AGEs can impact on organs and tissues affecting their functions and structure. This 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 diabetes, vascular complications of diabetes and other age-related diseases. Although therapies to treat MGO-associated complications are not yet available for application in clinical practice, several strategies to lower MGO have been developed over the years. We will summarize several new directions to target MGO stress including glyoxalase inducers and MGO scavengers. Diminishing MGO burden can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role.

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“…Increased levels of GO and MGO observed in diabetes and aging are biologically relevant as they induce cell senescence in human vascular endothelial cells (ECs). A study by Santos et al demonstrated that a combination of GO and MGO is able to increase p21 expression and to arrest human vascular ECs in the G2-phase of the cell cycle, besides the increase of ROS and AGEs formation [65], which can be abrogated by antioxidant and dicarbonyl scavenger treatment [65].…”

Section: Dicarbonyl Stress In Agingmentioning

confidence: 99%

Dicarbonyl Stress at the Crossroads of Healthy and Unhealthy Aging

Nigro

Leone

Fiory

et al. 2019

Cells

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Dicarbonyl stress occurs when dicarbonyl metabolites (i.e., methylglyoxal, glyoxal and 3-deoxyglucosone) accumulate as a consequence of their increased production and/or decreased detoxification. This toxic condition has been associated with metabolic and age-related diseases, both of which are characterized by a pro-inflammatory and pro-oxidant state. Methylglyoxal (MGO) is the most reactive dicarbonyl and the one with the highest endogenous flux. It is the precursor of the major quantitative advanced glycated products (AGEs) in physiological systems, arginine-derived hydroimidazolones, which accumulate in aging and dysfunctional tissues. The aging process is characterized by a decline in the functional properties of cells, tissues and whole organs, starting from the perturbation of crucial cellular processes, including mitochondrial function, proteostasis and stress-scavenging systems. Increasing studies are corroborating the causal relationship between MGO-derived AGEs and age-related tissue dysfunction, unveiling a previously underestimated role of dicarbonyl stress in determining healthy or unhealthy aging. This review summarizes the latest evidence supporting a causal role of dicarbonyl stress in age-related diseases, including diabetes mellitus, cardiovascular disease and neurodegeneration.

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Dicarbonyls induce senescence of human vascular endothelial cells

Cited by 21 publications

References 32 publications

Endothelial cells from umbilical cord of women affected by gestational diabetes: A suitable in vitro model to study mechanisms of early vascular senescence in diabetes

Endothelial cells from umbilical cord of women affected by gestational diabetes: A suitable in vitro model to study mechanisms of early vascular senescence in diabetes

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

Dicarbonyl Stress at the Crossroads of Healthy and Unhealthy Aging

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