Open AccessEndothelial cellular senescence is inhibited by nitric oxide: Implications in atherosclerosis associated with menopause and diabetes
Author(s) -
Toshio Hayashi,
Hisako Matsui-Hirai,
Asaka Miyazaki-Akita,
Atsushi Fukatsu,
Jun Funami,
Qianming Ding,
Kamalanathan Sumitra,
Yoshiyuki Hattori,
Louis J. Ignarro,
Akihisa Iguchi
Publication year - 2006
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0607873103
Subject(s) - senescence , enos , citrulline , nitric oxide , transfection , endothelial dysfunction , endocrinology , biology , umbilical vein , arginine , medicine , nitric oxide synthase , chemistry , biochemistry , microbiology and biotechnology , amino acid , in vitro , gene
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 β-galactosidase (SA-β-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-β-gal positive cells and increased telomerase activity. The NOS inhibitorN G -nitro-l -arginine methyl ester (l -NAME) abolished the effect of eNOS transfection. The physiological concentration of 17β-estradiol activated hTERT, decreased SA-β-gal-positive cells, and caused cell proliferation. However, ICI 182780, an estrogen receptor-specific antagonist, andl -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 withl -arginine orl -citrulline of eNOS-transfected cells partially inhibited, and combination ofl -arginine andl -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, includingl -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.