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Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells

フォーマット:
論文
責任表示:
Ishikura, Kazuhide ; Misu, Hirofumi ; Kumazaki, Masafumi ; Takayama, Hiroaki ; Matsuzawa-Nagata, Naoto ; Tajima, Natsumi ; Chikamoto, Keita ; Lan, Fei ; Ando, Hitoshi ; Ota, Tsuguhito ; Sakurai, Masaru ; Takeshita, Yumie ; Kato, Kenichiro ; Fujimura, Akio ; Miyamoto, Ken-ichi ; Saito, Yoshiro ; Kameo, Satomi ; Okamoto, Yasuo ; Takuwa, Yoh ; Takahashi, Kazuhiko ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; Kaneko, Shuichi ; Takamaura, Toshinari
言語:
英語
出版情報:
Springer Verlag, 2014-09-01
著者名:
Ishikura, Kazuhide
Misu, Hirofumi
Kumazaki, Masafumi
Takayama, Hiroaki
Matsuzawa-Nagata, Naoto
Tajima, Natsumi
Chikamoto, Keita
Lan, Fei
Ando, Hitoshi
Ota, Tsuguhito
Sakurai, Masaru
Takeshita, Yumie
Kato, Kenichiro
Fujimura, Akio
Miyamoto, Ken-ichi
Saito, Yoshiro
Kameo, Satomi
Okamoto, Yasuo
Takuwa, Yoh
Takahashi, Kazuhiko
Kidoya, Hiroyasu
Takakura, Nobuyuki
Kaneko, Shuichi
Takamaura, Toshinari
続きを見る
掲載情報:
Diabetologia
ISSN:
0012-186x  CiNii Research  Webcat Plus  JAIRO
巻:
57
通号:
9
開始ページ:
1968
終了ページ:
1976
バージョン:
author
概要:
Aims/hypothesis 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/interpretation The hepatokine SeP may be a novel therapeutic target for impaired angiogenesis in type 2 diabetes. © 2014 Springer-Verlag Berlin Heidelberg. 続きを見る
URL:
http://hdl.handle.net/2297/39052
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