API

Relationship: 980

Title

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Peptide Oxidation leads to Decrease, GTPCH-1

Upstream event

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Peptide Oxidation

Downstream event

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Decrease, GTPCH-1

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Peptide Oxidation Leading to Hypertension adjacent Moderate Low

Taxonomic Applicability

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

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
All life stages High

Key Event Relationship Description

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Exposure to known inducers of oxidative stress such as cigarette smoke extract (AbdelGhany et al., under review) or peroxynitrite (Zhao et al., 2013) causes the loss of GTPCH-1 activity, resulting in decreased levels of tetrahydrobiopterin (BH4) and subsequent uncoupling of endothelial nitric oxide synthase (eNOS).

Evidence Supporting this KER

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Biological Plausibility

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Several studies demonstrated that GTPCH-1 is also affected by oxidative stress, which provides evidence for moderate biological plausibility. In vitro exposure to chemically synthesized peroxynitrite inhibited GTPCH-1 activity in a dose-dependent manner (Zhao et al., 2013). This inhibition as well as increased ubiquitination of GTPCH-1 were observed in cultured bovine aortic endothelial cells (BAECs) and streptozotocin-induced diabetes in mice following peroxynitrite treatment. Ubiquitination of GTPCH-1 leads to its degradation, which is equivalent to a decrease in GTPCH-1. In another study, GTPCH-1 levels were reduced by cigarette smoke extract (CSE) exposure in BAECs (AbdelGhany et al., under review). There is also evidence that CSE promoted GTPCH-1 degradation by increasing proteasomal activity. Furthermore, cardiac reperfusion patients experienced oxidative stress which was associated with reduced GTPCH-1 activity (Jayaram et al., 2015).

Empirical Evidence

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Include consideration of temporal concordance here

In a rat model of aortic coarctation-associated hypertension, increased ROS (1.75 nmol DCF/mg protein/min) and decreased GTPCH-1 protein expression (western blot band intensity of 0.0087±0.005) were observed (Cervantes-Pérez et al., 2012). However, following clofibrate treatment (100 mg/kg/day, 7 days), ROS was reduced by approximately 30% and GTPCH-1 band intensity increased to 0.0087±0.005. This study provides evidence that there is a dependent change between oxidative stress and GTPCH-1, but we found no dose-response relationship, so empirical support for this KER is weak.

Uncertainties and Inconsistencies

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No uncertainties or inconsistencies were found for this KER.

Quantitative Understanding of the Linkage

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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?

As the relationship between oxidative stress and GTPCH-1 is not well-studied, there is limited quantitative understanding of this linkage.

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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Several studies showed decreased GTPCH-1 activity and/or protein expression under oxidative stress in cardiac reperfusion patients, bovine endothelial cells, a mouse model of diabetes and a rat model of hypertension (Cervantes-Pérez et al., 2012; AbdelGhany et al., (under review); Jayaram et al., 2015; Zhao et al., 2013).

References

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AbdelGhany, T., Ismail, R., Elmahdy, M., Mansoor F, Zweier J, Lowe, F., and Zweier, JL. (2017). Cigarette Smoke Constituents Cause Endothelial Nitric Oxide Synthase Dysfunction and Uncoupling due to Depletion of Tetrahydrobiopterin with Degradation of GTP Cyclohydrolase.  Nitric Oxide (Under review)

Cervantes-Pérez, L.G., Ibarra-Lara, M. de la L., Escalante, B., Del Valle-Mondragón, L., Vargas-Robles, H., Pérez-Severiano, F., Pastelín, G., and Sánchez-Mendoza, M.A. (2012). Endothelial nitric oxide synthase impairment is restored by clofibrate treatment in an animal model of hypertension. Eur. J. Pharmacol. 685, 108–115.

Jayaram, R., Goodfellow, N., Zhang, M.H., Reilly, S., Crabtree, M., De Silva, R., Sayeed, R., and Casadei, B. (2015). Molecular mechanisms of myocardial nitroso-redox imbalance during on-pump cardiac surgery. Lancet Lond. Engl. 385 Suppl 1, S49

Zhao, Y., Wu, J., Zhu, H., Song, P., and Zou, M.-H. (2013). Peroxynitrite-dependent zinc release and inactivation of guanosine 5’-triphosphate cyclohydrolase 1 instigate its ubiquitination in diabetes. Diabetes 62, 4247–4256.