Relationship:948

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Key Event Relationship Overview

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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 Arterial Stiffness Directly Leads to Strong Moderate

Taxonomic Applicability

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

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.

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 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).

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 reduced 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.

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).

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.

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)

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).

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).

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?

Evidence Supporting Taxonomic Applicability

References