title: Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells.
abstract: OBJECTIVE
  Impaired angiogenesis induced by vascular endothelial growth factor (VEGF) resistance is a hallmark of vascular complications in type 2 diabetes; however, its molecular mechanism is not fully understood. We have previously identified selenoprotein P (SeP, encoded by the SEPP1 gene in humans) as a liver-derived secretory protein that induces insulin resistance. Levels of serum SeP and hepatic expression of SEPP1 are elevated in type 2 diabetes. Here, we investigated the effects of SeP on VEGF signalling and angiogenesis.
  
  
  METHODS
  We assessed the action of glucose on Sepp1 expression in cultured hepatocytes. We examined the actions of SeP on VEGF signalling and VEGF-induced angiogenesis in HUVECs. We assessed wound healing in mice with hepatic SeP overexpression or SeP deletion. The blood flow recovery after ischaemia was also examined by using hindlimb ischaemia model with Sepp1-heterozygous-knockout mice.
  
  
  RESULTS
  Treatment with glucose increased gene expression and transcriptional activity for Sepp1 in H4IIEC hepatocytes. Physiological concentrations of SeP inhibited VEGF-stimulated cell proliferation, tubule formation and migration in HUVECs. SeP suppressed VEGF-induced reactive oxygen species (ROS) generation and phosphorylation of VEGF receptor 2 (VEGFR2) and extracellular signal-regulated kinase 1/2 (ERK1/2) in HUVECs. Wound closure was impaired in the mice overexpressing Sepp1, whereas it was improved in SeP (-/-)mice. SeP (+/-)mice showed an increase in blood flow recovery and vascular endothelial cells after hindlimb ischaemia.
  
  
  CONCLUSIONS
  The hepatokine SeP may be a novel therapeutic target for impaired angiogenesis in type 2 diabetes.
authors.affiliation: Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Ishikura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Misu
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kumazaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takayama
authors.forename: Naoto
authors.initials: N
authors.lastname: Matsuzawa-Nagata
authors.forename: Natsumi
authors.initials: N
authors.lastname: Tajima
authors.forename: Keita
authors.initials: K
authors.lastname: Chikamoto
authors.forename: Fei
authors.initials: F
authors.lastname: Lan
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ando
authors.forename: Tsuguhito
authors.initials: T
authors.lastname: Ota
authors.forename: Masaru
authors.initials: M
authors.lastname: Sakurai
authors.forename: Yumie
authors.initials: Y
authors.lastname: Takeshita
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kato
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Satomi
authors.initials: S
authors.lastname: Kameo
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takuwa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kidoya
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takakura
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Toshinari
authors.initials: T
authors.lastname: Takamura
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011401:Promoter Regions, Genetic / Q000235:genetics; D051149:Selenoprotein P / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology
chemical_list: D051149:Selenoprotein P; D042461:Vascular Endothelial Growth Factor A; D005947:Glucose