title: Kisspeptin-10 induces endothelial cellular senescence and impaired endothelial cell growth.
abstract: The KPs (kisspeptins) are a family of multifunctional peptides with established roles in cancer metastasis, puberty and vasoconstriction. The effects of KPs on endothelial cells have yet to be determined. The aim of the present study was to investigate the effects of KP-10 on endothelial cell growth and the mechanisms underlying those effects. The administration of recombinant KP-10 into the hindlimbs of rats with ischaemia significantly impaired blood flow recovery, as shown by laser Doppler, and capillary growth, as shown using histology, compared with the controls. HUVECs (human umbilical vein endothelial cells) express the KP receptor and were treated with KP-10 in culture studies. KP-10 inhibited endothelial cell tube formation and proliferation in a significant and dose-dependent manner. The HUVECs treated with KP exhibited the senescent phenotype, as determined using a senescence-associated β-galactosidase assay, cell morphology analysis, and decreased Sirt1 (sirtuin 1) expression and increased p53 expression shown by Western blot analysis. Intriguingly, a pharmacological Rho kinase inhibitor, Y-27632, was found to increase the proliferation of HUVECs and to reduce the number of senescent phenotype cells affected by KP-10. In conclusion, KP-10 suppressed endothelial cells growth both in vivo and in vitro in the present study. The adverse effect of KP on endothelial cells was attributable, at least in part, to the induction of cellular senescence.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Usui
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Iso
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sasai
authors.forename: Takuya
authors.initials: T
authors.lastname: Mizukami
authors.affiliation: *Division of Cardiology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Yokohama City, Kanagawa 227-8501, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Mori
authors.affiliation: §Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: †Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Shioda
authors.affiliation: *Division of Cardiology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Yokohama City, Kanagawa 227-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D003097:Collateral Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007511:Ischemia / Q000503:physiopathology; D059648:Kisspeptins / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; C106628:KISS1 protein, human; D059648:Kisspeptins; D011725:Pyridines; D011994:Recombinant Proteins; C108830:Y 27632; D054460:rho-Associated Kinases