Relationship:992
Contents
Key Event Relationship Overview
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Description of Relationship
Upstream Event | Downstream Event/Outcome |
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Oxidative Stress, Increase | Akt/eNOS activity, Decrease |
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 |
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How Does This Key Event Relationship Work
Exposure to known inducers of oxidative stress causes the phosphorylation of Akt and eNOS, leading to a decrease in their activities. However, hydrogen peroxide has been reported to have conflicting effects depending on the dose and time (Hu et al., 2008).
Weight of Evidence
Biological Plausibility
Multiple experimental studies reported modulations in Akt and eNOS phosphorylation/activity following exposure to oxidative stress, thus providing strong biological plausibility for this key event relationship.
In human umbilical vein endothelial cells (HUVECs), peroxynitrite significantly inhibited Akt phosphorylation at Ser473 and Akt activity (Song et al., 2007, 2008; Zou et al., 2002). However, Zou et al. found that peroxynitrite increase eNOS phosphorylation at Ser1199, but decreased NO, suggesting eNOS phosphorylation may not dependent on Akt. Treatment of BAECs with SIN-1, a source of peroxynitrite anion, inhibited eNOS activity by 30% and Akt/eNOS phosphorylation (Das et al., 2014).
High glucose can also inhibit Akt phosphorylation (Song et al., 2008), which supports other studies in which eNOS phosphorylation was affected by glucose. HUVECs treated with methylglyoxal and high glucosed reduced eNOS bradyinin-stimulated eNOS activity via Ser1177 phosphorylation (Dhar et al., 2010), while hyperglycemia inhibited eNOS activity in bovine aortic endothelial cells (BAECs) (Du et al., 2001). In EA.hy926 endothelial cells, methylglyoxal reduced eNOS phosphorylation at Ser1177 (Su et al., 2013). High-fat diet wild-type mice had decreased Akt and eNOS phosphorylation compared to normal chow diet wild-type mice (Du et al., 2013).
Cigarette smoke extract (CSE) also inhibited Akt and eNOS in VEGF-stimulated HUVECs (Michaud et al., 2006). Myocardial ischemia decreased phosphorylated AKT and eNOS in spontaneously hypertension (SHR) rats compared to sham animals (Zhang et al., 2014).
Empirical Support for Linkage
Include consideration of temporal concordance here
There is moderate empirical support for this link as eNOS activity and reactive oxygen species (ROS) were modulated to several stressors.
Methylglyoxal (30 μM) and high glucose (25 mM) for 24 hours caused a increase in ROS (control: 0.75, MG: 1.25, HG: 1) and decrease in eNOS activity (control: 100%, MG: 50%, HG: 60%) in HUVECs (Dhar et al., 2010).
SIN-1 treatment for two hours increased ROS (100% to 300%) and decreased eNOS activity (100% to 70%) (Das et al., 2014).
The increase in ROS and decrease in eNOS after H2O2 (100 μmol/L) was reversed with the addition of simvastatin (1 μmol/L) and nifedipine (1 μmol/L) (Chen et al., 2010).
Uncertainties or Inconsistencies
There are many studies examining the effect of hydrogen peroxide (H2O2) on Akt/eNOS phosphorylation, but there are conflicting results. One study showed that H2O2 initially increased eNOS Ser1179 phosphorylation and activity but after the peak increase at 30 minutes, eNOS Ser1179 phosphorylation dramatically decreased (Hu et al., 2008). A similar trend was observed for Akt phosphorylation. However, one study that exposed cells to H2O2 for 30 minutes showed increased Akt/eNOS phosphorylation, but its H2O2 concentration was much higher 200 μM compared to 5 μM (Barbosa et al., 2013). Other studies include H2O2 (100 μM/L, 30 min) inhibited eNOS expression (Chen et al., 2010), H2O2 (400 uM, 30 min) increased eNOS phosphorylation at the inhibitory site Thr495 (Guterbaum, 2013), and H2O2 increasing eNOS phosphorylation at Ser1177 (Kumar et al., 2010). Due to these inconsistencies, H2O2 may not be applicable to this key event relationship.
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?