title: Intermittent high glucose implements stress-induced senescence in human vascular endothelial cells: role of superoxide production by NADPH oxidase.
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.
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors: Morihiko
authors: M
authors: Maeda
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors: Toshio
authors: T
authors: Hayashi
authors: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Natsumi
authors: N
authors: Mizuno
authors: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Yuichi
authors: Y
authors: Hattori
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors: Masafumi
authors: M
authors: Kuzuya
mesh_terms: D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
chemical_list: D013481:Superoxides; D019255:NADPH Oxidases; D005947:Glucose