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

Morihiko Maeda,Toshio Hayashi,Masafumi Kuzuya,Yuichi Hattori,Natsumi Mizuno,Gabriele Saretzki

doi:10.1371/journal.pone.0123169

Morihiko Maeda, Toshio Hayashi + Show 4 more

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https://doi.org/10.1371/journal.pone.0123169

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Journal: PloS one	Publication Date: Apr 16, 2015
Citations: 82	License type: CC BY 4.0

Affiliation: Nagoya University, University of Toyama

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.

Highlights

Senescence of vascular endothelial cells is an important contributor to the pathogenesis of human atherosclerosis [1]
When Human umbilical venous endothelial cells (HUVECs) were exposed to constant high glucose, there was a significant increase in SAβ-gal activity, a widely used quantitative marker for aging in vitro
Intermittent high glucose stimulus (IHG) increased these proteins significantly compared with the condition of normal glucose and tended to increase them than those by continuous high glucose stimuli

Summary

Introduction

Senescence of vascular endothelial cells is an important contributor to the pathogenesis of human atherosclerosis [1]. Numerous studies have shown that the senescent phenotype of endothelial cells can be transformed from anti-atherosclerotic to pro-atherosclerotic [2]. We have provided evidence that senescent endothelial cells are found in human atherosclerotic lesions. Intermittent High Glucose Induced Endothelial Senescence but not in nonatherosclerotic lesions [3]. The hallmark of diabetes is the presence of hyperglycemia, which can accelerate senescence in endothelial cells [5]. We have demonstrated that high glucose can induce endothelial cell senescence [3,6,7,8]. We previously reported that continuous high glucose stimulus causes endothelial senescence more markedly than hypertension or dyslipidemia stimulus [8]

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