Korean Diabetes J.  2010 Aug;34(4):211-219. 10.4093/kdj.2010.34.4.211.

O-GlcNAc Modification: Friend or Foe in Diabetic Cardiovascular Disease

• Karunakaran U
• Jeoung NH

• KMID: 2029873
• DOI: http://doi.org/10.4093/kdj.2010.34.4.211

Abstract

O-Linked beta-N-acetyl glucosaminylation (O-GlcNAcylation) is a dynamic post-translational modification that occurs on serine and threonine residues of cytosolic and nuclear proteins in all cell types, including those involved in the cardiovascular system. O-GlcNAcylation is thought to act in a manner analogous to protein phosphorylation. O-GlcNAcylation rapidly cycles on/off proteins in a time scale similar to that for phosphorylation/dephosphorylation of proteins. Several studies indicate that O-GlcNAc might induce nuclear localization of some transcription factors and may affect their DNA binding activities. However, at the cellular level, it has been shown that O-GlcNAc levels increase in response to stress and augmentation of this response suppresses cell survival. Increased levels of O-GlcNAc have been implicated as a pathogenic contributor to glucose toxicity and insulin resistance, which are major hallmarks of type 2 diabetes and diabetes-related cardiovascular complications. Thus, O-GlcNAc and its metabolic functions are not yet well-understood; focusing on the role of O-GlcNAc in the cardiovascular system is a viable target for biomedical investigation. In this review, we summarize our current understanding of the role of O-GlcNAc on the regulation of cell function and survival in the cardiovascular system.

Keyword

Acetylglucosaminidase; Diabetes mellitus, type 2; Glycosyltransferase; Vascular diseases

MeSH Terms

Acetylglucosaminidase
Cardiovascular Diseases
Cardiovascular System
Cell Survival
Cytosol
Diabetes Mellitus, Type 2
DNA
Friends
Glucose
Humans
Insulin Resistance
Nuclear Proteins
Phosphorylation
Protein Processing, Post-Translational
Proteins
Serine
Threonine
Transcription Factors
Vascular Diseases
Acetylglucosaminidase
DNA
Glucose
Nuclear Proteins
Proteins
Serine
Threonine
Transcription Factors

Figure

• 

  Fig. 1 Interplay between O-GlcNAcylation and protein phosphorylation. (A) O-GlcNAc modification is strongly dependent on the concentration of UDP-GlcNAc produced by the hexosamine biosynthetic pathway (HBP). OGT uses UDP-GlcNAc as a substrate for GlcNAcylation on protein serine and threonine residues. O-GlcNAcase (OGA) removes the O-GlcNAc moiety from O-GlcNAc-modified proteins. PUGNAC inhibits the activity of O-GlcNAcase. (B) O-GlcNAc modification is analogous to protein phosphorylation/dephosphorylation. Interplay between GlcNAcylation and phosphorylation can affect the activities or stabilities of the proteins, and both processes can occur on the same protein at proximal sites.

• 

  Fig. 2 A fraction (2-5%) of the glucose entering a cell is directed into the hexosamine biosynthesis pathway (HBP) pathway. GFAT (glutamine: fructose-6-phosphate amidotransferase) uses glutamine to convert fructose-6-phosphate into glucosamine-6-phosphate, which is then used for the synthesis of UDP-GlcNAc in the cell. Activation of the HBP pathway acts through Sp1 sites to increase plasminogen activator inhibitor-1 (PAI-1) and tumor growth factor-alpha expressions. At the same time, O-GlcNAc modification of endothelial nitric oxide synthase (eNOS) decreases its activity and nitric oxide (NO) production.

• 

  Fig. 3 Hyperglycemia-induced activation of O-linked N-acetyl glucosamine activates GPX1 and its binding to c-Abl and Arg kinases and protects the cell via the antioxidant response. Along with an increase in the antioxidant response, increased O-GlcNAcylation activates p38 MAPK phosphorylation with increased glucose transport. Increased O-GlcNAc formation also increases the level of mitochondrial Bcl2, which inhibits apoptosis and protects the cell during stress.

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