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.
Highlights
Redox balance in cells is maintained by an interplay between processes that produce reactive oxygen species (ROS) and processes that eliminate ROS
The results reported here show that increasing glucose 6-phosphate dehydrogenase (G6PD) activity by two different methods restores redox balance in ECs exposed to high glucose
High glucose caused a decrease in G6PD activity (Figure 1A) and NADPH level (Figure 1B)
Summary
Redox balance in cells is maintained by an interplay between processes that produce reactive oxygen species (ROS) and processes that eliminate ROS (antioxidants). Alterations in this highly regulated system may lead to cellular dysfunction or death. Cell culture models of diabetes, animal models of diabetes, and humans with diabetes have increased ROS [2,6,7,8,9] Both increased production of ROS, as well as decreased antioxidant function have been shown to mediate the increased accumulation of cellular ROS [7]. Altered antioxidants play a role in the elevated ROS levels in diabetes as follows
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