Relationship:952
Contents
Key Event Relationship Overview
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Description of Relationship
Upstream Event | Downstream Event/Outcome |
---|---|
GTPCH-1, Decrease | Tetrahydrobiopterin, Decrease |
AOPs Referencing Relationship
AOP Name | Type of Relationship | Weight of Evidence | Quantitative Understanding |
---|---|---|---|
Oxidative Stress Leading to Hypertension | Directly Leads to | Strong | Strong |
Taxonomic Applicability
Name | Scientific Name | Evidence | Links |
---|---|---|---|
Homo sapiens | Homo sapiens | NCBI | |
Bos taurus | Bos taurus | NCBI | |
Mus musculus | Mus musculus | NCBI | |
Rattus norvegicus | Rattus norvegicus | NCBI |
How Does This Key Event Relationship Work
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.
Weight of Evidence
Biological Plausibility
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 endothelial cell line sEnd.1 and mouse 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 Support for Linkage
Include consideration of temporal concordance here
Exposure to a wide range of stimuli led to a decrease in both GTPCH-1 activity and expression and BH4 levels, indicating strong empirical support between these two key events. An assumption that a decrease in GTPCH-1 activity and expression 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 (Ismail et al., 2015).
In BAECs, stimulation with 25 μM 4-hydroxy-2-nonenal decreased BH4 levels from 10 pmol/mg to 6.1 pmol/mg and GTPCH-1 activity from 27 pmol/hr/mg to 23 pmol/hr/mg (Whitsett et al., 2007).
In a rat hypertensive model, the decrease in GTPCH-1 protein expression (western blot band intensity of 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 or Inconsistencies
There are no uncertainties or inconsistencies.
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?
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 (Ismail et al., 2015), and 4-hydroxy-2-nonenal (Whitsett et al., 2007).
Evidence Supporting Taxonomic Applicability
The relationship between GTPCH-1 and BH4 is supported in humans (Jayaram et al., 2015), cows (Ismail et al., 2015; 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
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.
Ismail, R., Elmahdy, M., AbdelGhany, T., Lowe, F., and Zweier, J. (2015). Cigarette smoke constituents cause endothelial dysfunction due to oxidative depletion of tetrahydrobiopterin and activation of the ubiquitin proteasome system. Free Radic. Biol. Med. Under review.
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.