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Intermittent high glucose implements stress-induced senescence in human vascular endothelial cells: role of superoxide production by NADPH oxidase.

Maeda M, Hayashi T, Mizuno N, Hattori Y, Kuzuya M - PLoS ONE (2015)

Bottom Line: Impaired glucose tolerance characterized by postprandial hyperglycemia, which occurs frequently in elderly persons and represents an important preliminary step in diabetes mellitus, poses an independent risk factor for the development of atherosclerosis.Interestingly, in intermittent high glucose, this effect was more pronounced as well as increase of p21 and p16INK4a , senescence related proteins with DNA damage.However, telomerase was not activated and telomere length was not shortened, thus stress-induced senescence was shown.

View Article: PubMed Central - PubMed

Affiliation: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.

ABSTRACT
Impaired glucose tolerance characterized by postprandial hyperglycemia, which occurs frequently in elderly persons and represents an important preliminary step in diabetes mellitus, poses an independent risk factor for the development of atherosclerosis. Endothelial cellular senescence is reported to precede atherosclerosis. We reported that continuous high glucose stimulus causes endothelial senescence more markedly than hypertension or dyslipidemia stimulus. In the present study, we evaluated the effect of fluctuating glucose levels on human endothelial senescence. Constant high glucose increased senescence-associated-β-galactosidase (SA-β-gal) activity, a widely used marker for cellular senescence. Interestingly, in intermittent high glucose, this effect was more pronounced as well as increase of p21 and p16INK4a , senescence related proteins with DNA damage. However, telomerase was not activated and telomere length was not shortened, thus stress-induced senescence was shown. However, constant high glucose activated telomerase and shortened telomere length, which suggested replicative senescence. Intermittent but not constant high glucose strikingly up-regulated the expression of p22phox, an NADPH oxidase component, increasing superoxide. The small interfering RNA of p22phox undermined the increase in SA-β-gal activity induced by intermittent high glucose. Conclusively, intermittent high glucose can promote vascular endothelial senescence more than constant high glucose, which is in partially dependent on superoxide overproduction.

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Effect of high glucose on telomerase activity and telomere length in HUVECs.NG, constant normal glucose (5 mM); HG, constant high glucose (22 mM); and N/HG, 5 mM alternating with 22 mM glucose. (A) Telomerase activity was measured by the telomere repeat application protocol (trap) assay. The values of the three independent experiments are mean ± S.D. **p<0.01 vs. NG; ##p<0.01 vs. HG. (B) Telomere length was measured to evaluate the relationship to replicative senescence. The data shown represent the average of two independent experiments.
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pone.0123169.g004: Effect of high glucose on telomerase activity and telomere length in HUVECs.NG, constant normal glucose (5 mM); HG, constant high glucose (22 mM); and N/HG, 5 mM alternating with 22 mM glucose. (A) Telomerase activity was measured by the telomere repeat application protocol (trap) assay. The values of the three independent experiments are mean ± S.D. **p<0.01 vs. NG; ##p<0.01 vs. HG. (B) Telomere length was measured to evaluate the relationship to replicative senescence. The data shown represent the average of two independent experiments.

Mentions: The telomerase, a specialized ribonucleprotein transcriptase that is important for long-term eukaryotic cell proliferation and genomic stability to replenish the DNA at telomeres, was significantly decreased in a constant high-glucose environment (Fig 4A). Subsequently, telomere length, a likely index of biological aging, was shortened by 4 weeks, which we continued the culture with every 3 days changing the tissue culture medium up to 28 days. It suggested replicative senescence (Fig 4B). In contrast, both telomerase activity and telomere length remained unchanged after exposure of HUVECs to intermittent high glucose (Fig 4A and 4B).


Intermittent high glucose implements stress-induced senescence in human vascular endothelial cells: role of superoxide production by NADPH oxidase.

Maeda M, Hayashi T, Mizuno N, Hattori Y, Kuzuya M - PLoS ONE (2015)

Effect of high glucose on telomerase activity and telomere length in HUVECs.NG, constant normal glucose (5 mM); HG, constant high glucose (22 mM); and N/HG, 5 mM alternating with 22 mM glucose. (A) Telomerase activity was measured by the telomere repeat application protocol (trap) assay. The values of the three independent experiments are mean ± S.D. **p<0.01 vs. NG; ##p<0.01 vs. HG. (B) Telomere length was measured to evaluate the relationship to replicative senescence. The data shown represent the average of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400006&req=5

pone.0123169.g004: Effect of high glucose on telomerase activity and telomere length in HUVECs.NG, constant normal glucose (5 mM); HG, constant high glucose (22 mM); and N/HG, 5 mM alternating with 22 mM glucose. (A) Telomerase activity was measured by the telomere repeat application protocol (trap) assay. The values of the three independent experiments are mean ± S.D. **p<0.01 vs. NG; ##p<0.01 vs. HG. (B) Telomere length was measured to evaluate the relationship to replicative senescence. The data shown represent the average of two independent experiments.
Mentions: The telomerase, a specialized ribonucleprotein transcriptase that is important for long-term eukaryotic cell proliferation and genomic stability to replenish the DNA at telomeres, was significantly decreased in a constant high-glucose environment (Fig 4A). Subsequently, telomere length, a likely index of biological aging, was shortened by 4 weeks, which we continued the culture with every 3 days changing the tissue culture medium up to 28 days. It suggested replicative senescence (Fig 4B). In contrast, both telomerase activity and telomere length remained unchanged after exposure of HUVECs to intermittent high glucose (Fig 4A and 4B).

Bottom Line: Impaired glucose tolerance characterized by postprandial hyperglycemia, which occurs frequently in elderly persons and represents an important preliminary step in diabetes mellitus, poses an independent risk factor for the development of atherosclerosis.Interestingly, in intermittent high glucose, this effect was more pronounced as well as increase of p21 and p16INK4a , senescence related proteins with DNA damage.However, telomerase was not activated and telomere length was not shortened, thus stress-induced senescence was shown.

View Article: PubMed Central - PubMed

Affiliation: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.

ABSTRACT
Impaired glucose tolerance characterized by postprandial hyperglycemia, which occurs frequently in elderly persons and represents an important preliminary step in diabetes mellitus, poses an independent risk factor for the development of atherosclerosis. Endothelial cellular senescence is reported to precede atherosclerosis. We reported that continuous high glucose stimulus causes endothelial senescence more markedly than hypertension or dyslipidemia stimulus. In the present study, we evaluated the effect of fluctuating glucose levels on human endothelial senescence. Constant high glucose increased senescence-associated-β-galactosidase (SA-β-gal) activity, a widely used marker for cellular senescence. Interestingly, in intermittent high glucose, this effect was more pronounced as well as increase of p21 and p16INK4a , senescence related proteins with DNA damage. However, telomerase was not activated and telomere length was not shortened, thus stress-induced senescence was shown. However, constant high glucose activated telomerase and shortened telomere length, which suggested replicative senescence. Intermittent but not constant high glucose strikingly up-regulated the expression of p22phox, an NADPH oxidase component, increasing superoxide. The small interfering RNA of p22phox undermined the increase in SA-β-gal activity induced by intermittent high glucose. Conclusively, intermittent high glucose can promote vascular endothelial senescence more than constant high glucose, which is in partially dependent on superoxide overproduction.

Show MeSH
Related in: MedlinePlus