title: Endothelial cellular senescence is inhibited by nitric oxide: implications in atherosclerosis associated with menopause and diabetes.
abstract: Senescence may contribute to the pathogenesis of atherosclerosis. Although the bioavailability of nitric oxide (NO) is limited in senescence, the effect of NO on senescence and its relationship to cardiovascular risk factors have not been investigated fully. We studied these factors by investigating senescence-associated beta-galactosidase (SA-beta-gal) and human telomerase activity in human umbilical venous endothelial cells (HUVECs). Treatment with NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-aminoethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO) and transfection with endothelial NO synthase (eNOS) into HUVECs each decreased the number of SA-beta-gal positive cells and increased telomerase activity. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) abolished the effect of eNOS transfection. The physiological concentration of 17beta-estradiol activated hTERT, decreased SA-beta-gal-positive cells, and caused cell proliferation. However, ICI 182780, an estrogen receptor-specific antagonist, and L-NAME each inhibited these effects. Finally, we investigated the effect of NO bioavailability on high glucose-promoted cellular senescence of HUVECs. Inhibition by eNOS transfection of this cellular senescence under high glucose conditions was less pronounced. Treatment with L-arginine or L-citrulline of eNOS-transfected cells partially inhibited, and combination of L-arginine and L-citrulline with antioxidants strongly prevented, high glucose-induced cellular senescence. These data demonstrate that NO can prevent endothelial senescence, thereby contributing to the anti-senile action of estrogen. The ingestion of NO-boosting substances, including L-arginine, L-citrulline, and antioxidants, can delay endothelial senescence under high glucose. We suggest that the delay in endothelial senescence through NO and/or eNOS activation may have clinical utility in the treatment of atherosclerosis in the elderly.
authors.affiliation: Department of Geriatrics, Nagoya University Graduate School of Medicine, Tsuruma-cho 65, Showa-ku, Nagoya 466-8550, Japan. hayashi@med.nagoya-u.ac.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Hayashi
authors.forename: Hisako
authors.initials: H
authors.lastname: Matsui-Hirai
authors.forename: Asaka
authors.initials: A
authors.lastname: Miyazaki-Akita
authors.forename: Akiko
authors.initials: A
authors.lastname: Fukatsu
authors.forename: Jun
authors.initials: J
authors.lastname: Funami
authors.forename: Qun-Fang
authors.initials: QF
authors.lastname: Ding
authors.forename: Sumitra
authors.initials: S
authors.lastname: Kamalanathan
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
authors.forename: Akihisa
authors.initials: A
authors.lastname: Iguchi
mesh_terms: D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D003925:Diabetic Angiopathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D008593:Menopause; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D014162:Transfection
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D019098:Telomerase