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1 Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA; Research Service, Zablocki Veterans Affairs Medical Center, Milwaukee, WI, USA
2 Department of Biomedical Engineering, Marquette University, Milwaukee, WI, USA; Department of Pulmonary Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; Research Service, Zablocki Veterans Affairs Medical Center, Milwaukee, WI, USA
3 Department of Pulmonary Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
4 Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
5 Department of Mathematics, Statistics and Computer Science, Marquette University, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: mmerker{at}mcw.edu.
The objective was to examine the impact of chronic hyperoxic exposure (95% O2 for 48 hours) on intact bovine pulmonary arterial endothelial cell redox metabolism of 2,3,5,6-tetramethyl-1,4-benzoquinone (duroquinone, DQ). DQ or durohydroquinone (DQH2) were added to normoxic or hyperoxia-exposed cells in air-saturated medium, and the medium DQ concentrations were measured over 30 minutes. DQ disappeared from the medium when DQ was added, and appeared in the medium when DQH2 was added, such that after about 15 minutes, a steady state DQ concentration was approached that was ~ 4.5 times lower for the hyperoxia-exposed than the normoxic cells. The rate of DQ mediated reduction of the cell membrane impermeant redox indicator, potassium ferricyanide, (K3Fe(CN)63-), was also ~ 2 fold faster for the hyperoxia-exposed cells. Inhibitor studies and mathematical modeling suggested that in both normoxic and hyperoxia-exposed cells, NAD(P)H:quinone oxidoreductase 1 (NQO1) was the dominant DQ reductase and mitochondrial electron transport complex III the dominant DQH2 oxidase involved, and that the difference between the net effects of the cells on DQ redox status could be attributed primarily to a 2 - fold increase in the maximum NQO1 mediated DQ reduction rate in the hyperoxia-exposed cells. Accordingly, NQO1 protein and total activity were higher in hyperoxia-exposed than normoxic cell cytosolic fractions. One outcome for hyperoxia-exposed cells was enhanced protection from cell-mediated DQ redox cycling. The study demonstrates that exposure to chronic hyperoxia increases the capacity of pulmonary arterial endothelial cells to reduce DQ to DQH2 via an increase in NQO1 protein and activity.
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