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Relationship: 992

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Peptide Oxidation leads to Decrease, AKT/eNOS activity

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Peptide Oxidation

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Decrease, AKT/eNOS activity

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Peptide Oxidation Leading to Hypertension	adjacent	High	Moderate	Frazer Lowe (send email)	Not under active development	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
Bos taurus	Bos taurus	High	NCBI
Mus musculus	Mus musculus	Low	NCBI
Rattus norvegicus	Rattus norvegicus	Low	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Exposure to known inducers of oxidative stress causes the phosphorylation of AKT and eNOS, leading to a decrease in their activities.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Multiple experimental studies reported modulations in Akt and eNOS phosphorylation/activity following oxidative stress, thus providing strong biological plausibility for this key event relationship.

In HUVECs, peroxynitrite significantly inhibited AKT phosphorylation at Ser473 and AKT activity (Song et al., 2007, 2008; Zou et al., 2002). However, Zou et al. (2002) found that peroxynitrite increased eNOS phosphorylation at Ser1199, but decreased NO availability, suggesting eNOS phosphorylation may not depend on AKT. Treatment of BAECs with SIN-1, a source of peroxynitrite, inhibited eNOS activity by 30% and AKT/eNOS phosphorylation (Das et al., 2014).

High glucose concentrations can also inhibit AKT phosphorylation (Song et al., 2008). HUVECs treated with methylglyoxal and high concentrations of glucose exhibited reduced bradykinin-stimulated eNOS activity via Ser1177 phosphorylation (Dhar et al., 2010), while hyperglycemia inhibited eNOS activity in BAECs (Du et al., 2001). In EA.hy926 endothelial cells, methylglyoxal treatment results in reduced eNOS phosphorylation at Ser1177 (Su et al., 2013). High-fat diet-induced obesity in mice caused an increase in ROS and a reduction in AKT and eNOS phosphorylation compared to non-obese mice (Du et al., 2013).

Treatment with 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 Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Include consideration of temporal concordance here

Treatment with 30 μM methylglyoxal (MG) and 25 mM glucose (HG) for 24 hours caused an increase in ROS (measured by DCF fluorescence in arbitrary units; control: 0.77, MG: 1.2, HG: 1) and a decrease in eNOS activity (control: 100%, MG: 55%, HG: 66%) in HUVECs (Dhar et al., 2010). SIN-1 treatment for two hours increased ROS (100% to 290%) and decreased eNOS activity (100% to 70%) (Das et al., 2014). An increase in ROS and decrease in eNOS activity was observed following treatment with 100 μmol/L H₂O₂ (Chen et al., 2010). Another study showed that 5 μM H₂O₂ treatment 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. Treatment with 100 μM/L H₂O₂ for 30 minutes inhibited eNOS expression (Chen et al., 2010), assuming that eNOS expression translates to eNOS activity. Treatment with H₂O₂ (400 µM, 30 min) increased eNOS phosphorylation at the inhibitory site Thr495, suggesting eNOS activity decreased (Guterbaum, 2013).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

There are many studies examining the effect of H₂O₂ on AKT/eNOS phosphorylation, but there are conflicting results. Exposure to H₂O₂ for 30 minutes resulted in an increase in AKT/eNOS phosphorylation, but its concentration was much higher at 200 μM (Barbosa et al., 2013) compared to 5 μM in Hu et al. (2008). Another study found that treatment with 50 μM H₂O₂ increased eNOS phosphorylation at Ser1177 (Kumar et al., 2010). Results from studies with H₂O₂ as a source of ROS may not be universally applicable to this key event relationship.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

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?

Dhar et al. (2010) showed that an increase in ROS of >30% due to high glucose and methylglyoxal treatment was able to decrease eNOS activity, while Das et al. (2014) showed a three-fold increase in ROS led to a 30% reduction in eNOS activity. SIN-1, high glucose, methylglyoxal and H₂O₂ were demonstrated to modulate both key events at the same time.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The relationship between oxidative stress and decreased AKT/eNOS activity is supported by studies performed in humans, cows, mice and rats.

References

List of the literature that was cited for this KER description. More help

Barbosa, V.A., Luciano, T.F., Marques, S.O., Vitto, M.F., Souza, D.R., Silva, L.A., Santos, J.P.A., Moreira, J.C., Dal-Pizzol, F., Lira, F.S., et al. (2013). Acute exercise induce endothelial nitric oxide synthase phosphorylation via Akt and AMP-activated protein kinase in aorta of rats: Role of reactive oxygen species. Int. J. Cardiol. 167, 2983–2988.

Chen, X., Xu, J., Feng, Z., Fan, M., Han, J., and Yang, Z. (2010). Simvastatin combined with nifedipine enhances endothelial cell protection by inhibiting ROS generation and activating Akt phosphorylation. Acta Pharmacol. Sin. 31, 813–820.

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.

Das, A., Gopalakrishnan, B., Druhan, L.J., Wang, T.-Y., De Pascali, F., Rockenbauer, A., Racoma, I., Varadharaj, S., Zweier, J.L., Cardounel, A.J., et al. (2014). Reversal of SIN-1-induced eNOS dysfunction by the spin trap, DMPO, in bovine aortic endothelial cells via eNOS phosphorylation. Br. J. Pharmacol. 171, 2321–2334.

Du, J., Fan, L.M., Mai, A., and Li, J.-M. (2013a). Crucial roles of Nox2-derived oxidative stress in deteriorating the function of insulin receptors and endothelium in dietary obesity of middle-aged mice. Br. J. Pharmacol. 170, 1064–1077.

Du, X.L., Edelstein, D., Dimmeler, S., Ju, Q., Sui, C., and Brownlee, M. (2001). Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J. Clin. Invest. 108, 1341–1348.

Guterbaum, T.J., Braunstein, T.H., Fossum, A., Holstein-Rathlou, N.-H., Torp-Pedersen, C.T., and Domínguez, H. (2013). Endothelial nitric oxide synthase phosphorylation at Threonine 495 and mitochondrial reactive oxygen species formation in response to a high H₂O₂ concentration. J. Vasc. Res. 50, 410–420.

Hu, Z., Chen, J., Wei, Q., and Xia, Y. (2008). Bidirectional actions of hydrogen peroxide on endothelial nitric-oxide synthase phosphorylation and function: co-commitment and interplay of Akt and AMPK. J. Biol. Chem. 283, 25256–25263.

Kumar, S., Sud, N., Fonseca, F.V., Hou, Y., and Black, S.M. (2010). Shear stress stimulates nitric oxide signaling in pulmonary arterial endothelial cells via a reduction in catalase activity: role of protein kinase C delta. Am. J. Physiol. Lung Cell. Mol. Physiol. 298, L105–L116.

Michaud, S.E., Dussault, S., Groleau, J., Haddad, P., and Rivard, A. (2006). Cigarette smoke exposure impairs VEGF-induced endothelial cell migration: role of NO and reactive oxygen species. J. Mol. Cell. Cardiol. 41, 275–284.

Song, P., Wu, Y., Xu, J., Xie, Z., Dong, Y., Zhang, M., and Zou, M.-H. (2007). Reactive nitrogen species induced by hyperglycemia suppresses Akt signaling and triggers apoptosis by upregulating phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) in an LKB1-dependent manner. Circulation 116, 1585–1595.

Song, P., Xie, Z., Wu, Y., Xu, J., Dong, Y., and Zou, M.-H. (2008). Protein kinase Czeta-dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells. J. Biol. Chem. 283, 12446–12455.

Su, Y., Qadri, S.M., Wu, L., and Liu, L. (2013). Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells. Cardiovasc. Diabetol. 12, 134.

Zhang, W., Han, Y., Meng, G., Bai, W., Xie, L., Lu, H., Shao, Y., Wei, L., Pan, S., Zhou, S., et al. (2014). Direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion injury by activating nitric oxide synthase signaling in spontaneously hypertensive rats. J. Am. Heart Assoc. 3, e000606.

Zou, M.-H., Hou, X.-Y., Shi, C.-M., Nagata, D., Walsh, K., and Cohen, R.A. (2002). Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. J. Biol. Chem. 277, 32552–32557.