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

Abstract

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.

• Authors: Kazuhide Ishikura, Hirofumi Misu, Masafumi Kumazaki, Hiroaki Takayama, Naoto Matsuzawa-Nagata, Natsumi Tajima, Keita Chikamoto, Fei Lan, Hitoshi Ando, Tsuguhito Ota, Masaru Sakurai, Yumie Takeshita, Kenichiro Kato, Akio Fujimura, Ken-Ichi Miyamoto, Yoshiro Saito, Satomi Kameo, Yasuo Okamoto, Yoh Takuwa, Kazuhiko Takahashi, Hiroyasu Kidoya, Nobuyuki Takakura, Shuichi Kaneko, Toshinari Takamura
• Journal: Diabetologia (Diabetologia) Vol. 57 Issue 9 Pg. 1968-76 (Sep 2014) ISSN: 1432-0428 [Electronic] Germany
• PMID: 24989996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Selenoprotein P
• Vascular Endothelial Growth Factor A
• Glucose

Topics

• Animals
• Cell Proliferation (genetics, physiology)
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Endothelial Cells (metabolism)
• Glucose (metabolism)
• Hepatocytes (metabolism)
• Human Umbilical Vein Endothelial Cells
• Mice
• Mice, Knockout
• Mice, Mutant Strains
• Promoter Regions, Genetic (genetics)
• Selenoprotein P (genetics, metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Wound Healing (genetics, physiology)