title: 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.
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Zhaoyun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
authors.forename: Bo
authors.initials: B
authors.lastname: Zhu
authors.forename: Ji
authors.initials: J
authors.lastname: Hu
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.forename: Yingyi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jane A
authors.initials: JA
authors.lastname: Leopold
authors.forename: Diane E
authors.initials: DE
authors.lastname: Handy
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
authors.forename: Robert C
authors.initials: RC
authors.lastname: Stanton
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology*; D005947:Glucose / Q000494:pharmacology*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D005954:Glucosephosphate Dehydrogenase; D019255:NADPH Oxidases; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose