title: Bradykinin inhibits serum-depletion-induced apoptosis of human vascular endothelial cells by inducing nitric oxide via calcium ion kinetics.
abstract: Vascular endothelial cells play important roles in atherogenesis, and bradykinin is associated with atherosclerosis. The effect of bradykinin on apoptosis in human umbilical vein endothelial cells (HUVECs) was investigated, with a focus on Ca2+ kinetics and nitric oxide production. In serum-free conditions, the number of apoptotic cells increased in a time-dependent manner, but this increase was inhibited by bradykinin in a dose-dependent manner. The apoptosis inhibited by bradykinin was reduced by nitric oxide inhibitor N(G)-monomethyl-L-arginine (L-NMMA) and consequently restored by combined treatment with L-NMMA and L-arginine. Bradykinin increased influx of extracellular Ca2+, generation of inositol 1,4,5-trisphosphate, and release of Ca2+ from intracellular storage sites, thus increasing the total intracellular Ca2+ concentration ([Ca2+]i). Bradykinin increased nitric oxide production, which was inhibited by L-NMMA and restored by combined treatment with L-NMMA and L-arginine. Sodium nitroprusside (SNP) dose-dependently increased nitric oxide production and inhibited apoptosis; however, 10(-5) M SNP did not inhibit apoptosis. Caspase-3 inhibitor, acetyl-Asp-Met-Gln-Asp-aldehyde, enhanced bradykinin-induced inhibition of apoptosis but did not effect bradykinin-induced nitric oxide production. These findings suggest that bradykinin inhibits serum-depletion-induced apoptosis in HUVECs by enhancing nitric oxide production via an increase in [Ca2+]i.
authors.affiliation: Second Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. sawada@koto.kpu-m.ac.jp
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kono
authors.forename: Shohei
authors.initials: S
authors.lastname: Sawada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawahara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Tadashi
authors.initials: T
authors.lastname: Higaki
authors.forename: Seiki
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Imamura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tada
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sato
authors.forename: Osamu
authors.initials: O
authors.lastname: Hiranuma
authors.forename: Naoaki
authors.initials: N
authors.lastname: Akamatsu
authors.forename: Sumio
authors.initials: S
authors.lastname: Komatsu
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tamagaki
authors.forename: Katsumi
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Hajime
authors.initials: H
authors.lastname: Tsuji
authors.forename: Masao
authors.initials: M
authors.lastname: Nakagawa
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001920:Bradykinin / Q000494:pharmacology* / Q000502:physiology; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D053148:Caspase 3; D061945:Caspase Inhibitors; D002413:Cations, Divalent; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D002413:Cations, Divalent; D016895:Culture Media, Serum-Free; D015853:Cysteine Proteinase Inhibitors; D020030:Nitric Oxide Donors; D009842:Oligopeptides; C110922:acetyl-aspartyl-methionyl-glutaminyl-aspartyl-aldehyde; D009599:Nitroprusside; D009569:Nitric Oxide; D015544:Inositol 1,4,5-Trisphosphate; C505407:CASP3 protein, human; D053148:Caspase 3; D001920:Bradykinin; D002118:Calcium