title: High glucose induces human endothelial dysfunction through an Axl-dependent mechanism.
abstract: BACKGROUND
  The receptor tyrosine kinase Axl and its ligand growth arrest-specific protein 6 (Gas6) are involved in the diabetic vascular disease. The aim of this study was to explore the role of Gas6/Axl system in high glucose (HG)-induced endothelial dysfunction.
  
  
  METHODS
  We investigated the effect of various glucose concentrations on Axl signaling in human microvascular endothelial cells (HMEC-1 s).
  
  
  RESULTS
  Human plasma Gas6 value inversely correlated with glucose status, endothelial markers. HG decreased Gas6/Axl expression and increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in HMEC-1 s. HG significantly decreased HMEC-1 s cell viability and tube formation and promoted monocyte-EC adhesion. Down-regulation of Akt phosphorylation was found in HG culture. Axl transfection significantly reversed HG-induced Akt phosphorylation, VCAM-1 expression and endothelial dysfunction. We also found additive changes in Axl-shRNA-infected HMEC-1 cells in HG culture. Furthermore, Axl overexpression in HMEC-1 s significantly reversed HG-induced vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression. In addition, significantly lower Axl and VEGFR2 expression in arteries were found in diabetic patients as compared with non-diabetic patients.
  
  
  CONCLUSIONS
  This study demonstrates that HG can alter Gas6/Axl signaling and may through Akt and VEGF/VEGFR2 downstream molecules and suggests that Gas6/Axl may involve in HG-induced EC dysfunction.
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Lee
authors.forename: Yi-Shing
authors.initials: YS
authors.lastname: Shieh
authors.forename: Fone-Ching
authors.initials: FC
authors.lastname: Hsiao
authors.forename: Feng-Chih
authors.initials: FC
authors.lastname: Kuo
authors.forename: Chih-Yuan
authors.initials: CY
authors.lastname: Lin
authors.forename: Chang-Hsun
authors.initials: CH
authors.lastname: Hsieh
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, #325, Section 2, Cheng-Gong Rd,, Nei-Hu, Taipei, Taiwan. metahung@yahoo.com.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Hung
mesh_terms: D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000633:toxicity*; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D005947:Glucose; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722289:AXL protein, human