Difference between revisions of "Relationship:948"

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|[[Aop:149|Oxidative Stress Leading to Arterial Stiffness]]||Directly Leads to||[[Relationship:948#Weight of Evidence|Strong]]||[[Relationship:948#Quantitative Understanding of the Linkage|Moderate]]
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|[[Aop:149|Oxidative Stress Leading to Hypertension]]||Directly Leads to||[[Relationship:948#Weight of Evidence|Strong]]||[[Relationship:948#Quantitative Understanding of the Linkage|Moderate]]
  
 
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|Bos taurus||Bos taurus||||[http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9913 NCBI]
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|Bos taurus||Bos taurus||[[Relationship:948#Evidence Supporting Taxonomic Applicability|Weak]]||[http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9913 NCBI]
  
 
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|Rattus norvegicus||Rattus norvegicus||||[http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116 NCBI]
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|Rattus norvegicus||Rattus norvegicus||[[Relationship:948#Evidence Supporting Taxonomic Applicability|Weak]]||[http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116 NCBI]
  
 
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== How Does This Key Event Relationship Work ==
 
== How Does This Key Event Relationship Work ==
Under physiological conditions, glutathione (GSH) functions as an anti-oxidant by defending the cell from products of 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 context. Exposure to oxidants like peroxides leads to the oxidation of intracellular reduced GSH, resulting in the formation of GSSG which alters the redox state of the cell (Pullar et al., 2001). This imbalance in GSH/GSSG ratio is a marker of oxidative stress and contributes to endothelial dysfunction.
+
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.
  
 
== Weight of Evidence ==
 
== Weight of Evidence ==
 
=== Biological Plausibility ===
 
=== Biological Plausibility ===
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 support for their 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 methylglycoxal 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 aortical endothelial cells, respectively (De Pascali et al., 2014; Du et al., 2013).  
+
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 (H<sub>2</sub>O<sub>2</sub>), 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).
  
 
=== Empirical Support for Linkage ===
 
=== Empirical Support for Linkage ===
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</em>
 
</em>
  
The following studies demonstrated a dose-dependent relationship between known inducers of oxidative stress and reduced GSH levels; therefore the empirical support for this link is moderate.
+
The following studies demonstrated a dose-dependent relationship between known inducers of oxidative stress and GSH levels; therefore, the empirical support for this link is moderate.
  
Tert-butyl hydroperoxide treatment (0.1 mM) decreased GSH levels immediately after one minute to 30% of the resting value (van Gorp et al., 1999). The percentage of reduced GSH slowly increased to 41% after 10 minutes and to 68% after 60 minutes, but did not fully restore to 100% . Higher concentration of tBH led to more severe GSH oxidation.
+
Tert-butyl hydroperoxide treatment (0.1 mM) decreased GSH levels immediately after one minute to 30% of the resting value (van Gorp et al., 1999). The percentage of GSH slowly increased to 41% after 10 minutes and to 68% after 60 minutes, but did not fully restore to 100%. Higher concentrations of tBH led to more severe GSH oxidation.
  
Treatment of HUVECs with H202 (0.01-1 mM) caused a dose-dependent decrease in GSH levels after 15 minutes followed by a slow recovery phase (Montecinos et al., 2007).
+
Treatment of HUVECs with H<sub>2</sub>O<sub>2</sub> (0.01-1 mM) caused a dose-dependent decrease in GSH levels after 15 minutes followed by a slow recovery phase (Montecinos et al., 2007).
  
Methylglyoxal (30 μM) and high glucose (25 mM) for 24 hours significantly increased ROS levels and reduced GSH levels in HUVECs and rat aortic endothelial cells (Dhar et al., 2010), showing a dependency between oxidative stress and GSH oxidation following a perturbation.
+
Methylglyoxal (30 μM) and high concentrations of glucose (25 mM) significantly increased ROS levels and reduced GSH levels in HUVECs and rat aortic endothelial cells after 24 hours (Dhar et al., 2010), showing a dependency between oxidative stress and GSH oxidation.
  
Exposure to ultrafine particles (diameter<200nm) for 6 hours at 50 μg/mL led decreased GSH levels from 17.1±1.8 μM to 12.0±2.4 μM and increased GSSG from 0.62±0.26 μM to 1.60±0.2 μM in human aortic endothelia cells (Du et al., 2013)
+
Exposure to 50 μg/mL ultrafine particles (diameter<200nm) for 6 hours led to a decrease in GSH levels from 17.1±1.8 μM to 12.0±2.4 μM and an increase in GSSG from 0.62±0.26 μM to 1.60±0.2 μM in human aortic endothelial cells (Du et al., 2013)
  
In HUVECs, H2O2 treatment at doses of 100 μM, 200 μM, and 300 μM increased ROS production to 150%, 125% and 200%, respectively compared to control. This dose-dependent change also occurs with the percentage of GSH depletion at 21% depletion at 200 μM H2O2 and 22% depletion at 300 μM H202 (Park et al., 2013).  
+
In HUVECs, H<sub>2</sub>O<sub>2</sub> treatment at doses of 100 μM, 200 μM, and 300 μM increased ROS production to 152%, 130% and 182%, respectively compared to control. This dose-dependent change was accompanied by GSH depletion (21.3% depletion at 200 μM H<sub>2</sub>O<sub>2</sub> and 21.4% depletion at 300 μM H<sub>2</sub>O<sub>2</sub>) (Park et al., 2013).
  
 
=== Uncertainties or Inconsistencies ===
 
=== Uncertainties or Inconsistencies ===
One study reported that only a small amount of GSH were oxidized to GSSG in a concentration-dependent manner when exposed to hypochlorous acid (HOCl) in HUVECs while the rest of GSH were converted to another product glutathione sulfonamide. This discrepancy may be due to different oxidant used in this study as well as the lower sublethal concentration of HOCl compared to other studies (25 nmol HOCl compared to 0.1 to 1 mM hydrogen peroxide) (Pullar et al., 2001).
+
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).
  
 
== Quantitative Understanding of the Linkage ==
 
== Quantitative Understanding of the Linkage ==
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</em>
 
</em>
  
From the studies mentioned above, it appears that any oxidant (e.g. tBH, H2O2, ultrafine particles) with a minimum concentration of 200 μM would be sufficient to induce oxidation of GSH and cause an increase in GSSG levels as shown in Park et al. study where a dose of 200μM H2O2 was able to cause a dose-dependent change in ROS and reduced GSH levels. However, treatment with a smaller concentration like 25 nM of HOCl was shown to oxidize GSH, but did not produce GSSG but rather another product (Pullar et al., 2001). Oxidation of GSH was measured as early as one minute after tBH exposure, but GSH levels slowly restored after 10 minutes (van Gorp et al., 1999). Exposure to H2O2 demonstrated that GSH levels can be decreased after 15 minutes (Montecinos et al., 2007), after 1 hour, and even at 24 hour (Park et al., 2013).
+
From the studies mentioned above, it appears that any oxidant (e.g. tBH, H<sub>2</sub>O<sub>2</sub>, ultrafine particles) with a minimum concentration of 10 μM would be sufficient to induce oxidation of GSH and cause an increase in GSSG levels. However, treatment with a concentration of25 nM of HOCl was shown to oxidize GSH, but did not produce GSSG (Pullar et al., 2001).
  
 
== Evidence Supporting Taxonomic Applicability ==
 
== Evidence Supporting Taxonomic 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).
  
 
== References ==
 
== References ==
  
 
<references />
 
<references />
 +
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.

Latest revision as of 13:51, 2 July 2016


Key Event Relationship Overview

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If you manually enter text in this section, it will get automatically altered or deleted in subsequent edits using the widgets.

Description of Relationship

Upstream Event Downstream Event/Outcome
Oxidative Stress, Increase Glutathione, Oxidation

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Oxidative Stress Leading to Hypertension Directly Leads to Strong Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links
Homo sapiens Homo sapiens Strong NCBI
Bos taurus Bos taurus Weak NCBI
Rattus norvegicus Rattus norvegicus Weak NCBI

How Does This Key Event Relationship Work

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.

Weight of Evidence

Biological Plausibility

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).

Empirical Support for Linkage

Include consideration of temporal concordance here

The following studies demonstrated a dose-dependent relationship between known inducers of oxidative stress and GSH levels; therefore, the empirical support for this link is moderate.

Tert-butyl hydroperoxide treatment (0.1 mM) decreased GSH levels immediately after one minute to 30% of the resting value (van Gorp et al., 1999). The percentage of GSH slowly increased to 41% after 10 minutes and to 68% after 60 minutes, but did not fully restore to 100%. Higher concentrations of tBH led to more severe GSH oxidation.

Treatment of HUVECs with H2O2 (0.01-1 mM) caused a dose-dependent decrease in GSH levels after 15 minutes followed by a slow recovery phase (Montecinos et al., 2007).

Methylglyoxal (30 μM) and high concentrations of glucose (25 mM) significantly increased ROS levels and reduced GSH levels in HUVECs and rat aortic endothelial cells after 24 hours (Dhar et al., 2010), showing a dependency between oxidative stress and GSH oxidation.

Exposure to 50 μg/mL ultrafine particles (diameter<200nm) for 6 hours led to a decrease in GSH levels from 17.1±1.8 μM to 12.0±2.4 μM and an increase in GSSG from 0.62±0.26 μM to 1.60±0.2 μM in human aortic endothelial cells (Du et al., 2013)

In HUVECs, H2O2 treatment at doses of 100 μM, 200 μM, and 300 μM increased ROS production to 152%, 130% and 182%, respectively compared to control. This dose-dependent change was accompanied by GSH depletion (21.3% depletion at 200 μM H2O2 and 21.4% depletion at 300 μM H2O2) (Park et al., 2013).

Uncertainties or 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).

Quantitative Understanding of the Linkage

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

From the studies mentioned above, it appears that any oxidant (e.g. tBH, H2O2, ultrafine particles) with a minimum concentration of 10 μM would be sufficient to induce oxidation of GSH and cause an increase in GSSG levels. However, treatment with a concentration of25 nM of HOCl was shown to oxidize GSH, but did not produce GSSG (Pullar et al., 2001).

Evidence Supporting Taxonomic 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).

References

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.