title: Dose-dependent modulatory effects of insulin on glucose-induced endothelial senescence in vitro and in vivo: a relationship between telomeres and nitric oxide.
abstract: The elderly are prone to postprandial hyperglycemia that increases their cardiovascular risk. Although insulin therapy is necessary to treat diabetes, high plasma concentrations of insulin may cause the development of atherosclerosis and accelerate endothelial senescence. We assumed that high glucose causes stress-induced premature senescence and replicative senescence and examined the regulatory role of insulin in endothelial senescence and functions under different glucose conditions. Exposure of human endothelial cells to high glucose (22 mM) for 3 days increased senescence-associated-β-galactosidase activity, a senescence marker, and decreased telomerase activity, a replicative senescence marker. Physiological concentrations of insulin preserved telomere length and delayed endothelial senescence under high-glucose conditions. The effect of insulin under high-glucose conditions was associated with reduced reactive oxygen species and increased nitric oxide (NO). Small interfering RNA targeting endothelial NO synthase reduced the antisenescence effects of insulin. Physiological concentrations of insulin also reversed high glucose-induced increases in p53 and vascular cell adhesion molecule-1 and decreases in senescence marker protein-30. On the other hand, when insulin was given at any concentrations under normal glucose or at high concentrations under high glucose, its ability to promote cellular senescence was unrelated to endothelial NO. Finally, streptozotocin-induced diabetes showed more senescent cells in the aortic endothelium of aged rats compared with age-matched control and insulin-treated animals. Conclusively, the regulatory effects of insulin on endothelial senescence were modulated by the glucose environment. These data may help explain insulin's complicated roles in atherosclerosis in the elderly.
authors.affiliation: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Matsui-Hirai
authors.forename: Toshio
authors.initials: T
authors.lastname: Hayashi
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ina
authors.forename: Morihiko
authors.initials: M
authors.lastname: Maeda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kotani
authors.forename: Akihisa
authors.initials: A
authors.lastname: Iguchi
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001011:Aorta; D050197:Atherosclerosis / Q000503:physiopathology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000502:physiology*; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D034741:RNA, Small Interfering; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019098:Telomerase; D001616:beta-Galactosidase; D005947:Glucose