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Abstract
BackgroundThe 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.MethodsWe investigated the effect of various glucose concentrations on Axl signaling in human microvascular endothelial cells (HMEC-1 s).ResultsHuman 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.ConclusionsThis 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.
Highlights
The receptor tyrosine kinase Axl and its ligand growth arrest-specific protein 6 (Gas6) are involved in the diabetic vascular disease
high glucose (HG) concentrations and Gas6/Axl, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in HMEC-1 s To determine whether HG affects Gas6/Axl, ICAM-1 and VCAM-1 expression in Endothelial cell (EC), HMEC-1 s were cultured in 5, 20 and 40 mM glucose and equimolar concentrations of mannitol for 24 h
The effect of D-glucose on these proteins expression was not secondary to osmotic load. These data showed that HG leads to a decrease in Gas6/Axl mRNA and protein level in HMEC-1 s, which likely contributes to endothelial dysfunction with increased ICAM-1 and VCAM-1 proteins expression
Summary
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. Dysfunction of Growth arrest-specific protein 6 (Gas6) belongs to the family of vitamin K-dependent coagulation proteins and is recognized as a growth factor-like molecule, as it interacts with receptor tyrosine kinases of the TAM (Tyro-3, Axl, Mer) family [7]. The role of the Gas6/TAM system has been found to be important in injury, repair, inflammation, hemostasis, autoimmune disease, vascular systems, and cancer [8]. Numerous studies have identified the pivotal role Gas plays in vascular biology and diseases [9,10]. Gas and its receptors are involved in the pathogenesis of neointima formation, vasculitis and atherosclerosis [11,12,13,14]
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