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Relationship: 952

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

Decrease, GTPCH-1 leads to Decrease, Tetrahydrobiopterin

Upstream event

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

Decrease, GTPCH-1

Downstream event

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

Decrease, Tetrahydrobiopterin

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	High	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	High	NCBI
Rattus norvegicus	Rattus norvegicus	High	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

Guanosine triphosphate cyclohydrolase-1 (GTPCH-1) is the rate-limiting enzyme in the de novo biosynthesis of BH4, which is an essential cofactor for eNOS and NO generation (Wang et al., 2008). Oxidative stress can disrupt and decrease GTPCH-1 activity, leading to decreased BH4 levels and subsequent uncoupling of eNOS.

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

As GTPCH-1 is required for BH4 biosynthesis, there is strong biological plausibility for this relationship.

Many studies demonstrated that deletion of GTPCH-1 led to the deficiency of BH4 in endothelial cells. In the hph-1 mouse model, cardiac GTPCH-1 enzymatic activity was reduced by 90% compared to wild-type mice, which led to 60% reduction in BH4 levels (Adlam et al., 2012). In another mouse model of endothelial-targeted deletion of GTPCH-1, BH4 levels in lung, heart and aorta were significantly decreased compared to wild-type mice (Chuaiphichai et al., 2014). GTPCH-1 siRNA significantly reduced GTPCH-1 enzyme activity and BH4 levels in murine sEnd.1 and aortic endothelial cells (Crabtree et al., 2009; Tatham et al., 2009; Wang et al., 2008). The selective GTPCH-1 inhibitor diaminohydroxypyrimidine (DAHP) reduced levels of BH4 in bovine aortic endothelial cells (BAECs) (Wang et al., 2008). Also, transgenic overexpression of GTPCH-1 increased BH4 protein levels in murine hearts and aortas, leading to enhanced eNOS activity (Alp et al., 2003; Carnicer et al., 2012).

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

Exposure to a wide range of stimuli led to a decrease in both GTPCH-1 expression and activity and a decrease in BH4 levels, indicating strong empirical support between these two key events. An assumption that a decrease in GTPCH-1 expression and activity also results in a decrease in BH4 levels was made for these studies.

After myocardial reperfusion, GTPCH-1 activity decreased from 100% to 50% and arterial BH4 levels was reduced by 32% (Jayaram et al., 2015).

IL6/TNF/LPS (4 ng/mL, 10 nmol/L, 80 ng/mL) stimulation for 24 hours induced a 3-fold upregulation of GTPCH-1 gene expression and 3- to 4-fold increase in vascular BH4 (Antoniades et al., 2011). For this evidence, an assumption that a change in GTPCH-1 gene expression would affect GTPCH-1 enzyme activity was made.

Cigarette smoke extract (CSE, 5%) exposure for 4 hours significantly decreased BH4 levels from 100% to 50% and GTPCH-1 expression from 100% to 51%, while a lower concentration of 2.5% CSE did not cause a significant change in bovine aortic endothelial cells (Abdelghany et al., 2017).

In BAECs, stimulation with 25 μM 4-hydroxy-2-nonenal decreased BH4 levels from 10 pmol/mg protein to 6.1 pmol/mg protein and GTPCH-1 activity from 27 pmol/hr/mg protein to 23 pmol/hr/mg protein (Whitsett et al., 2007).

In a rat hypertensive model, the decrease in GTPCH-1 protein expression (via densitometry of western blot band intensity, 0.089 control to 0.0087) and BH4 (33.71±3.318 pmol control to 17.144±2.251 pmol) induced by aortic coarctation was attenuated by clofibrate treatment (GTPCH-1: 0.088±0.022 band intensity, BH4: 32.534±5.809 pmol) (Cervantes-Pérez et al., 2012).

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 no uncertainties or inconsistencies.

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?

Based on the relationship between GTPCH-1 and BH4, it would be possible that any change in GTPCH-1 activity would affect BH4 biosynthesis. The studies above showed that there are many modulators of the response-response relationships including cardiac reperfusion (Jayaram et al., 2015), cytokines (Antoniades et al., 2011), CSE (Abdelghany et al., 2017), and 4-hydroxy-2-nonenal (Whitsett et al., 2007).

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 GTPCH-1 and BH4 is supported in humans (Jayaram et al., 2015), cows (Abdelghany et al., 2017; Whitsett et al., 2007, Wang et al., 2008), mice (Adlam et al., 2012; Chuaiphichai et al., 2014; Crabtree et al., 2009; Tatham et al., 2009; Wang et al., 2008) and rats (Cervantes-Pérez et al., 2012).

References

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

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).

Adlam, D., Herring, N., Douglas, G., De Bono, J.P., Li, D., Danson, E.J., Tatham, A., Lu, C.-J., Jennings, K.A., Cragg, S.J., et al. (2012). Regulation of β-adrenergic control of heart rate by GTP-cyclohydrolase 1 (GCH1) and tetrahydrobiopterin. Cardiovasc. Res. 93, 694–701.

Alp, N.J., Mussa, S., Khoo, J., Cai, S., Guzik, T., Jefferson, A., Goh, N., Rockett, K.A., and Channon, K.M. (2003). Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. J. Clin. Invest. 112, 725–735.

Antoniades, C., Cunnington, C., Antonopoulos, A., Neville, M., Margaritis, M., Demosthenous, M., Bendall, J., Hale, A., Cerrato, R., Tousoulis, D., et al. (2011). Induction of vascular GTP-cyclohydrolase I and endogenous tetrahydrobiopterin synthesis protect against inflammation-induced endothelial dysfunction in human atherosclerosis. Circulation 124, 1860–1870.

Carnicer, R., Hale, A.B., Suffredini, S., Liu, X., Reilly, S., Zhang, M.H., Surdo, N.C., Bendall, J.K., Crabtree, M.J., Lim, G.B.S., et al. (2012). Cardiomyocyte GTP cyclohydrolase 1 and tetrahydrobiopterin increase NOS1 activity and accelerate myocardial relaxation. Circ. Res. 111, 718–727.

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.

Chen, C.-A., Lin, C.-H., Druhan, L.J., Wang, T.-Y., Chen, Y.-R., and Zweier, J.L. (2011). Superoxide induces endothelial nitric-oxide synthase protein thiyl radical formation, a novel mechanism regulating eNOS function and coupling. J. Biol. Chem. 286, 29098–29107.

Chuaiphichai, S., McNeill, E., Douglas, G., Crabtree, M.J., Bendall, J.K., Hale, A.B., Alp, N.J., and Channon, K.M. (2014). Cell-autonomous role of endothelial GTP cyclohydrolase 1 and tetrahydrobiopterin in blood pressure regulation. Hypertension 64, 530–540.

Crabtree, M.J., Tatham, A.L., Al-Wakeel, Y., Warrick, N., Hale, A.B., Cai, S., Channon, K.M., and Alp, N.J. (2009). Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cells with tet-regulated GTP cyclohydrolase I expression. J. Biol. Chem. 284, 1136–1144.

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.

Tatham, A.L., Crabtree, M.J., Warrick, N., Cai, S., Alp, N.J., and Channon, K.M. (2009). GTP cyclohydrolase I expression, protein, and activity determine intracellular tetrahydrobiopterin levels, independent of GTP cyclohydrolase feedback regulatory protein expression. J. Biol. Chem. 284, 13660–13668.

Wang, S., Xu, J., Song, P., Wu, Y., Zhang, J., Chul Choi, H., and Zou, M.-H. (2008). Acute inhibition of guanosine triphosphate cyclohydrolase 1 uncouples endothelial nitric oxide synthase and elevates blood pressure. Hypertension 52, 484–490.

Whitsett, J., Picklo, M.J., and Vasquez-Vivar, J. (2007). 4-Hydroxy-2-nonenal increases superoxide anion radical in endothelial cells via stimulated GTP cyclohydrolase proteasomal degradation. Arterioscler. Thromb. Vasc. Biol. 27, 2340–2347.