O-GlcNAcylation of connexin 40: a sweet connection between diabetes and endothelial cell dysfunction? Focus on “O-GlcNAcase overexpression reverses coronary endothelial cell dysfunction in type 1 diabetic mice”

Abstract

CARDIOVASCULAR COMPLICATIONS are the leading cause of morbidity and mortality in patients with diabetes mellitus. The vascular alterations that develop in diabetic patients relate to the pathogenesis of both macrovascular (increased incidence and severity of stroke and myocardial infarction) and microvascular (neuropathy, nephropathy, retinopathy, and erectile dysfunction) systems. Endothelial dysfunction has been implicated in the development of macro-and microvascular diseases. Chronic hyperglycemia is believed to constitute a major contributing factor to the pathogenesis of vascular complications in diabetic patients. Among the various mechanisms that have been involved in the so-called glucotoxicity phenomenon, O-linked N-acetylglucosaminylation (O-GlcNAcylation) of proteins is emerging as an important player (for review see Ref. 5).O-GlcNAcylation is a posttranslational reversible modification that involves the addition of N-acetylglucosamine (GlcNAc) on serine or threonine residues of cytosolic and nuclear proteins. Only two enzymes, O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and ␤-N-acetylglucosaminidase (OGA), regulate O-GlcNAc level on protein according to glucose availability (Fig. 1). O-GlcNAcylation has been shown to control the activity, subcellular localization, and stability of numerous proteins, including transcription factors, metabolic enzymes, and signaling molecules. O-GlcNAcylation can also control the phosphorylation of proteins, either by directly competing with the phosphate group for the same residue (yin-yang mechanism) or by regulating the phosphorylation of nearby residues (5).Nitric oxide (NO), the principal endothelium-dependent relaxing factor, is a key component of vascular homeostasis. In diabetes, endothelial cells fail to produce sufficient amounts of NO and induce vasorelaxation in response to endotheliumdependent vasorelaxants (e.g., acetylcholine, bradykinin, and shear stress) (1). Several studies have implicated O-GlcNAc in the deleterious effects of diabetes on NO production. Endothelial NO synthase (eNOS), the enzyme responsible for NO production in endothelial cells, is activated via its phosphorylation on S1177 by Akt. In bovine and rat aortic endothelial cells, as well as human coronary artery endothelial cells, high glucose resulted in increased O-GlcNAc on eNOS and decreased phosphorylation of the protein on the Akt site, suggesting a reciprocal relationship between eNOS phosphorylation and O-GlcNAcylation (5). In addition, Musicki et al. (10), studying erectile function in diabetic rat penis, also observed increased O-GlcNAcylation of eNOS, associated with decreased phosphorylation on S1177 and reduced erectile response to shear stress or VEGF, providing a potential mechanism for diabetes-associated erectile dysfunction. Moreover, Lima et al. (6), using rat artery segments, showed that OGlcNAcylation induced by O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino N-phenylcarbamate (PugNAc), an inhibitor of OGA, blunted vascular reactivity to the vasore...

O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension

“…Glucose flux through the HBP has been linked to impaired angiogenesis and vascular dysfunction in many metabolic disorders including diabetes and cancer [30,35,58,59,65,[67][68][69][70]. However, the mechanisms have not been completely defined.…”

The Pathogenic Role of Very Low Density Lipoprotein on Atrial Remodeling in the Metabolic Syndrome

“…Besides down-regulation of gap junction proteins and gene expression, MetS-VLDL was found to also modulate the Cx40 and Cx43 proteins with enhanced O-GlcNAylation, which is postulated to affect the gap junction assembly and stability by interfering with the electrostatic balance on neighbor molecule interaction [82]. The O-GlcNAylation of Cx40 under high glucose condition has been reported to affect gap junction in endothelial cells [83]. Our report was the first to demonstrate the VLDL-induced O-GlcNAylation of Cx40 and Cx43 in atrial myocyte HL-1 cells.…”

Very-Low-Density Lipoprotein of Metabolic Syndrome Modulates Gap Junctions and Slows Cardiac Conduction

“…O-GlcNAcylation can also regulate the phosphorylation of Cx40 and Cx43. Evidence has shown a contribution of O-GlcNAcylation to endothelial dysfunction in diabetes mellitus and in hyperglycemia-associated cardiovascular defects 18 , 19 . The O-GlcNAcylation of Cx40 or Cx43 in atrial myocytes has not been explored.…”