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Peptide Oxidation leads to Oxidation, Glutathione
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Under physiological conditions, glutathione (GSH) functions as an anti-oxidant by defending the cell from oxidative stress (Kalinina et al., 2014). It is predominantly found in the reduced form while the oxidized form glutathione disulfide (GSSG) generally does not exceed 1% of its total cellular content. Exposure to oxidants like peroxides leads to the oxidation of intracellular GSH, resulting in the formation of GSSG which alters the redox state of the cell (Pullar et al., 2001). This imbalance in the GSH/GSSG ratio is a marker of oxidative stress.
Evidence Supporting this KER
Multiple studies demonstrated that oxidative stress leads to the oxidation of GSH in the vascular endothelium, thus providing extensive understanding of the mechanistic relationship between these key events and strong biological plausibility. Exposure of human umbilical endothelial cells (HUVECs) to tert-butyl hydroperoxide (tBH), hydrogen peroxide (H2O2), and diamide caused a decrease in levels of GSH, which is indicative of its oxidation to GSSG (Montecinos et al., 2007; Park et al., 2013; Schuppe et al., 1992; van Gorp et al., 2002, 1999). Treatment with methylglyoxal and glucose also significantly reduced GSH levels in HUVECs and rat aortic endothelial cells (Dhar et al., 2010). Additional support for this link was observed in studies following ischemia-reperfusion injury and ultrafine particle exposure in bovine aortic endothelial cells and human aortic endothelial cells, respectively (De Pascali et al., 2014; Du et al., 2013).
Uncertainties and Inconsistencies
One study reported that only a small amount of GSH was oxidized to GSSG in a concentration-dependent manner when HUVECs were exposed to hypochlorous acid (HOCl) while the remaining GSH was converted to another product glutathione sulfonamide. This discrepancy may be due to the different oxidant used in this study (Pullar et al., 2001).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
There are many studies showing oxidation of GSH following oxidant exposure in human endothelial cells, particularly umbilical and aortic endothelial cells (Dhar et al., 2010; Du et al., 2013; Montecinos et al., 2007; Park, 2013; Schuppe et al., 1992; van Gorp et al., 1999, 2002), while two studies in rat and bovine aortic endothelial cells support this relationship (Dhar et al., 2010; De Pascali et al., 2014).
De Pascali, F., Hemann, C., Samons, K., Chen, C.-A., and Zweier, J.L. (2014). Hypoxia and reoxygenation induce endothelial nitric oxide synthase uncoupling in endothelial cells through tetrahydrobiopterin depletion and S-glutathionylation. Biochemistry (Mosc.) 53, 3679–3688.
Dhar, A., Dhar, I., Desai, K.M., and Wu, L. (2010). Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose. Br. J. Pharmacol. 161, 1843–1856.
Du, Y., Navab, M., Shen, M., Hill, J., Pakbin, P., Sioutas, C., Hsiai, T.K., and Li, R. (2013). Ambient ultrafine particles reduce endothelial nitric oxide production via S-glutathionylation of eNOS. Biochem. Biophys. Res. Commun. 436, 462–466.
Kalinina, E.V., Chernov, N.N., and Novichkova, M.D. (2014). Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes. Biochem. Biokhimii︠a︡ 79, 1562–1583.
Montecinos, V., Guzmán, P., Barra, V., Villagrán, M., Muñoz-Montesino, C., Sotomayor, K., Escobar, E., Godoy, A., Mardones, L., Sotomayor, P., et al. (2007). Vitamin C is an essential antioxidant that enhances survival of oxidatively stressed human vascular endothelial cells in the presence of a vast molar excess of glutathione. J. Biol. Chem. 282, 15506–15515.
Park, W.H. (2013). The effects of exogenous H2O2 on cell death, reactive oxygen species and glutathione levels in calf pulmonary artery and human umbilical vein endothelial cells. Int. J. Mol. Med. 31, 471–476.
Pullar, J.M., Vissers, M.C., and Winterbourn, C.C. (2001). Glutathione oxidation by hypochlorous acid in endothelial cells produces glutathione sulfonamide as a major product but not glutathione disulfide. J. Biol. Chem. 276, 22120–22125.
Schuppe, I., Moldéus, P., and Cotgreave, I.A. (1992). Protein-specific S-thiolation in human endothelial cells during oxidative stress. Biochem. Pharmacol. 44, 1757–1764.
van Gorp, R.M.A., Heeneman, S., Broers, J.L.V., Bronnenberg, N.M.H.J., van Dam-Mieras, M.C.E., and Heemskerk, J.W.M. (2002). Glutathione oxidation in calcium- and p38 MAPK-dependent membrane blebbing of endothelial cells. Biochim. Biophys. Acta 1591, 129–138.
van Gorp, R.M., Broers, J.L., Reutelingsperger, C.P., Bronnenberg, N.M., Hornstra, G., van Dam-Mieras, M.C., and Heemskerk, J.W. (1999). Peroxide-induced membrane blebbing in endothelial cells associated with glutathione oxidation but not apoptosis. Am. J. Physiol. 277, C20–C28.