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Long Chain Lipid Hydroperoxides Increase the Glutathione Redox Potential Through Glutathione Peroxidase 4
Citation:
Corteselli, E., E. Gibbs-Flournoy, Steve Simmons, P. Bromberg, A. Gold, AND James M. Samet. Long Chain Lipid Hydroperoxides Increase the Glutathione Redox Potential Through Glutathione Peroxidase 4. Biochimica et Biophysica Acta. Elsevier Science Ltd, New York, NY, 1863(5):950-959, (2019). https://doi.org/10.1016/j.bbagen.2019.03.002
Impact/Purpose:
This is a peer-reviewed research article that reports findings from a study of the mechanisms by which oxidant pollutants dysregulate redox homeostasis in cells. The data describe biochemical changes that occur in cells exposed to a fatty acid derivative produced during exposure to oxidant stressors such as the air pollutant ozone. Given that oxidant stress is a common mechanism of action in toxicology and that many environmental agents present an oxidant stress to cells, the findings this research article represent an extension in our understanding of the toxicology of xenobiotics at a fundamental level.
Description:
Background Peroxidation of PUFAs by a variety of endogenous and xenobiotic electrophiles is a recognized pathophysiological process that can lead to adverse health effects. Although secondary products generated from peroxidized PUFAs have been relatively well studied, the role of primary lipid hydroperoxides in mediating early intracellular oxidative events is not well understood. Methods Live cell imaging was used to monitor changes in glutathione (GSH) oxidation in HAEC expressing the fluorogenic sensor roGFP during exposure to 9-hydroperoxy-10E,12Z-octadecadienoic acid (9-HpODE), a biologically important long chain lipid hydroperoxide, and its secondary product 9-hydroxy-10E,12Z-octadecadienoicacid (9-HODE). The role of hydrogen peroxide (H02 2) was examined by direct measurement and through catalase interventions.shRNA-mediated knockdown of glutathione peroxidase 4 (GPX4) was utilized to determine its involvement in the relay through which 9-HpODE initiates the oxidation of GSH. Results Exposure to 9-HpODE caused a dose-dependent increase in GSH oxidation in HAEC that was independent of intracellular or extracellular H202 production and was exacerbated by NADPH depletion. GPX4 was involved in the initiation of GSH oxidation in HAEC by 9-HpODE, but not that induced by exposure to H20 2 or the low molecular weight alkyl tert-butyl hydroperoxide (TBH). Conclusions Long chain lipid hydroperoxides can directly alter cytosolic " independent of secondary lipid oxidation products or H20 2 prodµction. NADPH has a protective role against 9-HpODE induced "changes. GPX4 is involved specifically in the reduction of long-chain lipid hydroperoxides, leading to GSH oxidation.· Significance These results reveal a previously unrecognized consequence of lipid peroxidation, which may provide insight into disease states involving lipid peroxidation in their pathogenesis
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DOI: Long Chain Lipid Hydroperoxides Increase the Glutathione Redox Potential Through Glutathione Peroxidase 4