Increasing Glucose 6-Phosphate Dehydrogenase Activity Restores Redox Balance in Vascular Endothelial Cells Exposed to High Glucose

Abstract

Previous studies have shown that high glucose increases reactive oxygen species (ROS) in endothelial cells that contributes to vascular dysfunction and atherosclerosis. Accumulation of ROS is due to dysregulated redox balance between ROS-producing systems and antioxidant systems. Previous research from our laboratory has shown that high glucose decreases the principal cellular reductant, NADPH by impairing the activity of glucose 6-phosphate dehydrogenase (G6PD). We and others also have shown that the high glucose-induced decrease in G6PD activity is mediated, at least in part, by cAMP-dependent protein kinase A (PKA). As both the major antioxidant enzymes and NADPH oxidase, a major source of ROS, use NADPH as substrate, we explored whether G6PD activity was a critical mediator of redox balance. We found that overexpression of G6PD by pAD-G6PD infection restored redox balance. Moreover inhibition of PKA decreased ROS accumulation and increased redox enzymes, while not altering the protein expression level of redox enzymes. Interestingly, high glucose stimulated an increase in NADPH oxidase (NOX) and colocalization of G6PD with NOX, which was inhibited by the PKA inhibitor. Lastly, inhibition of PKA ameliorated high glucose mediated increase in cell death and inhibition of cell growth. These studies illustrate that increasing G6PD activity restores redox balance in endothelial cells exposed to high glucose, which is a potentially important therapeutic target to protect ECs from the deleterious effects of high glucose.

Biochemical and cellular properties of Gluconacetobacter xylinus cultures exposed to different modes of rotating magnetic field

“…The synthesis of gluconic acid in bacteria is conducted by membrane-bound glucose dehydrogenase (GDH) 28 . As reported by Zheng et al 36 the magnetic fi eld of a specifi c frequency can increase the activity of this enzyme. Therefore, it can be assumed that the differences in the concentration of gluconic acid observed in the present study could be a result of variances in GDH activity caused by the particular mode of RMF exposure.…”

Diminished COX-2/PGE2-Mediated Antiviral Response Due to Impaired NOX/MAPK Signaling in G6PD-Knockdown Lung Epithelial Cells

“…Consistent with this report, we have observed that G6PD knockdown markedly decreased the expression level of NOX subunits in parallel with an absence of NOX induction by TNF-α. G6PD can control nuclear NADPHdependent superoxide production by NOX4 [43], and G6PD is colocalized with NOX in high G6PD Status Affects TNF-α-Triggered COX-2 Response glucose conditions, while providing NADPH for NOX activation [44] is an additional evidence to support the hypothesis that G6PD can modulate NOX activity. Physiologically, the activation of NOX can trigger the production of chemokines and inflammation-associated proteins upon viral infection [19,45,46].…”

High glucose–induced ubiquitination of G6PD leads to the injury of podocytes

“…However, G6PD deficiency will cripple the antioxidant defense, resulting in the build‐up of ROS and subsequent oxidative damage. Previously, we and others showed that G6PD deficiency led to increased accumulation of ROS in many cell types, which impaired their cellular function and survival (18, 21). In this study, we report for the first time that high glucose–induced G6PD deficiency in podocytes resulted in increased ROS accumulation and apoptosis, which could be rescued by overexpressing G6PD.…”