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Protein modification by O-linked GlcNAc reduces angiogenesis by inhibiting Akt activity in endothelial cells

Bai Luo1, Yudi Soesanto, Donald A McClain

  • 1Division of Endocrinology, University of Utah, Salt Lake City, UT 84132, USA.

Arteriosclerosis, Thrombosis, and Vascular Biology
|January 5, 2008
PubMed
Abstract

Insights

Elevated O-linked N-acetylglucosamine (O-GlcNAc) modification, driven by the hexosamine biosynthesis pathway (HBP), impairs blood vessel formation (angiogenesis). This suggests a new target for treating diabetic vascular complications.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Vascular Biology

Background:

  • Diabetic vascular complications are linked to glucose metabolism via the hexosamine biosynthesis pathway (HBP).
  • Protein O-linked N-acetylglucosamine (O-GlcNAc) modification is a key mediator of HBP activity.
  • Diabetes is associated with impaired angiogenesis, but underlying mechanisms require further elucidation.

Purpose of the Study:

  • To investigate the role of protein O-GlcNAc modification in regulating angiogenesis.
  • To determine if O-GlcNAc modification impacts endothelial cell function relevant to blood vessel formation.

Main Methods:

  • Mouse aortic ring assay to assess angiogenesis.
  • In vitro studies using human umbilical vein endothelial cells and EA.hy926 cells.
  • Manipulation of O-GlcNAc levels using glucosamine and O-GlcNAcase overexpression.
  • Western blot analysis to detect O-GlcNAc modification and Akt activity.

Main Results:

  • Elevated O-GlcNAc levels, induced by diabetes or glucosamine, correlated with impaired angiogenesis in aortic ring assays.
  • Glucosamine treatment increased O-GlcNAc modification, inhibiting endothelial cell migration and capillary-like structure formation.
  • Overexpression of O-GlcNAcase reversed these inhibitory effects.
  • High glucose concentrations also reduced capillary-like structure formation.
  • Increased O-GlcNAc modification of Akt was associated with reduced Akt activity.

Conclusions:

  • Elevated protein O-GlcNAc modification within the HBP negatively impacts angiogenesis in endothelial cells.
  • Inhibition of Akt signaling by O-GlcNAc modification may be a key mechanism underlying impaired angiogenesis in diabetes.

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