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Event: 1269

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, COX-2 expression

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Increase, COX-2 expression
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
eukaryotic cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
gene expression prostaglandin G/H synthase 2 increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
AhR mediated mortality, via COX-2 KeyEvent Markus Hecker (send email) Open for citation & comment WPHA/WNT Endorsed

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Danio rerio Danio rerio High NCBI
Oryzias latipes Oryzias latipes High NCBI
Gallus gallus Gallus gallus High NCBI
mouse Mus musculus High NCBI
human Homo sapiens Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Embryo High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

COX Pathway:

https://aopwiki.org/system/dragonfly/production/2017/05/08/7vmvnr8r73_COX_pathway.pdf

  • Prostaglandin-endoperoxide synthase (PTGS; KEGG ID E.C. 1.14.99.1) is an enzyme that has two catalytic sites.
  • Cyclooxygenase site (COX) catalyzes conversion of arachidonic acid into endoperoxide prostaglandin G2 (Simmons et al 2004).
  • Peroxidase active site converts PGG2 to PGH2 (KEGG reactions 1599, 1590). PGH2 is a precursor for synthesis of other prostaglandins (PGEs, PGFs), prostacyclin, and thromboxanes (Simmons et al 2004; Botting & Botting 2011).
  • There are two isoforms, COX-1 and COX-2
  • COX-2 is inducible by certain chemical exposures, inflammation, during discrete stages of gamete maturation, and more (Green et al 2012).
  • However, COX biology is complex and important details of the pathway remain unknown (Grosser 2006).

COX Cardiovascular Roles:

  • Prostaglandins which are catalyzed by COX and have roles in cellular homeostasis and in promoting inflammatory responses (Chien et al 2015; Smith et al 2000; Tilley et al 2001; Vane et al 1994).
  • Significant evidence suggests a link between COX-2 mediated inflammatory responses and progression of alterations in cardiovascular development and function in murine models, humans, and zebrafish (Danio rerio) (Delgado et al 2004; Gullestad & Aukrust 2005; Hocherl et al 2002; Huang et al 2007; Wong et al 1998 ).
  • However, the precise mechanism by which prostaglandins produce alterations in cardiovascular development have not been clearly elucidated (Hocherl & Dreher 2002).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help
  • COX-2 can be measured as abundance of transcript by use of quantitative real-time polymerase chain reaction (q-RT PCR). Transcript abundance of COX-2 has been measured in whole embryos of fishes (Dong et al 2010; Huang et al 2007; Teraoka et al 2008; 2014) and embryonic hepatic and cardiac tissue of birds (Fujisawa et al 2014).
  • COX-2 could be measured by use of ELISA or Western Blot, but commercial kits are not currently available for fishes or birds.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

COX-2 Structure and Function:

  • There is a high level of conservation of COX-2, as well as its function, especially across vertebrates (Havird et al 2008; 2015), indicating that numerous vertebrate taxa might be susceptible to up-regulation in COX-2.
  • Typically, teleost fish genomes contain more than one COX-2 gene, likely a result of genome duplication after divergence of teleosts from tetrapods (Ishikawa et al 2007; Havird et al 2015). In zebrafish there are two isoforms, COX-2a and COX-2b (Teraoka et al 2014).
  • In invertebrates, COX is found in most crustaceans, the majority of molluscs, but only in specific lineages within Cnidaria and Annelida. COX genes are not found in Hemichordata, Echinodermata, or Platyhelminthes. Insecta COX genes lack in homology, but might function as COX enzymes based on structural analyses (Havird et al 2015).

References

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

Bacchi, S., Palumbo, P., Sponta, A., & Coppolino, M. F. (2012). Clinical pharmacology of non-steroidal anti-inflammatory drugs: a review. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Inflammatory and Anti-Allergy Agents), 11(1), 52-64.

Botting, R. M., & Botting, J. H. (2011). C14 Non-steroidal anti-inflammatory drugs. In Principles of Immunopharmacology (pp. 573-584). Birkhäuser Basel.

Chien, P.; Lin, C.; Hsiao, L.; Yang, C. (2015). c-SRC/Pyk2/EGFR/PI3K/Akt/CREB-activated pathway contributes to human cardiomyocyte hypertrophy: Role of COX-2 induction. Mol. Cell. Endocrin. 409. 59-72.

Chandrasekharan, N. V., Dai, H., Roos, K. L. T., Evanson, N. K., Tomsik, J., Elton, T. S., & Simmons, D. L. (2002). COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proceedings of the National Academy of Sciences,99(21), 13926-13931.

Crofford, L.J. (1997). COX-1 and COX-2 tissue expression: implications and predictions. J. Rheumatol. Suppl. 49, 15-90.

Degner, S.C.; Kemp, M.Q.; Hockings, J.K.; Romagnolo, D.F. (2007). Cyclooxygenase-2 promoter activation by the aromatic hydrocarbon receptor in breast cancer MCF-7 cells: Repressive effects of conjugated linoleic acid. Nutri. Canc. 56 (2), 248-257.

Delgado R.; Newar, M.; Zewail, A.; Kar, B.; Vaughn, W.; Wu, K.; Aleksic, N,; Sivasubramanian, N.; McKay, K.; Mann, D. (2004). Cyclooxygenase-2 inhibitor treatment improves left ventricle function and mortality in a murine model of doxorubicin-induced heart failure. Circulation. 109, 1428-1433.

Dong, W.; Matsumura, F.; Kullman, S.W. (2010). TCDD induced pericardial edema and relative COX-2 expression in medaka (Oryzias latipes) embryos. Toxicol. Sci. 118 (1), 213-223.

Fujisaw, N.; Nakayama, S.M.M.; Ikenaka, Y.; Ishizuka, M. 2014. TCDD-induced chick cardiotoxicity is abolished by a selective cyclooxygenase-2 (COX-2) inhibitor NS398. Arch. Toxicol. 88, 1739-1748.

Gullestad, L.; Aukrust, P. (2005). Review of trials in chronic heart failure showing broad-spectrum anti-inflammatory approaches. Am. J. Cardiol. 95, 17C-23C; discussion 38C-40C.

Havird, J. C., Kocot, K. M., Brannock, P. M., Cannon, J. T., Waits, D. S., Weese, D. A., ... & Halanych, K. M. (2015). Reconstruction of Cyclooxygenase Evolution in Animals Suggests Variable, Lineage-Specific Duplications, and Homologs with Low Sequence Identity. Journal of molecular evolution, 1-16.

Havird, J. C., Miyamoto, M. M., Choe, K. P., & Evans, D. H. (2008). Gene duplications and losses within the cyclooxygenase family of teleosts and other chordates. Molecular biology and evolution, 25(11), 2349-2359.

Hocherl, K.; Dreher, F.; Kurtz, A.; Bucher, M. (2002). Cyclooxygenase-2 inhibition attenuates liposaccaride-induced cardiovascular failure. Hypertension. 40, 947-953.

Huang, C.; Chen, P., Huang, C.; Yu J. (2007). Aristolochic acid induces heart failure in zebrafish embryos that is mediated by inflammation. Toxicol, Sci. 100 (2), 486-494.

Ishikawa, T. O., Griffin, K. J., Banerjee, U., & Herschman, H. R. (2007). The zebrafish genome contains two inducible, functional cyclooxygenase-2 genes.Biochemical and biophysical research communications, 352(1), 181-187.

Jonsson, M.E.; Kubota, A.; Timme-Laragy, A.R.; Woodin, B.; Stegeman, J.J. (2012). Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish. Toxicol. Appl. Pharmacol. 265 (2), 166-174.

Picot, D.; Loll, P.J.; Garavito, R.M. (1994). The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature. 367 (6460), 243-290.

Simmons, D. L., Botting, R. M., & Hla, T. (2004). Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacological reviews,56(3), 387-437.

Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem. 2000; 69: 145–182.

Streicher, J.M.; Kamei, K.; Ishikawa, T.; Herschman, H.; Wang, Y. (2010). Compensatory hypertrophy induced by ventricular cardiomyocyte specific COX-2 expression in mice. J. Mol. Cell. Cardiol. 49 (1), 88-94.

Teraoka, H.; Kubota, A.; Kawai, Y.; Hiraga, T. (2008). Prostanoid signaling mediates circulation failure caused by TCDD in developing zebrafish. Interdis. Studies Environ. Chem. Biol. Resp. Chem. Pollut. 61-80.

Teraoka, H.; Okuno, Y.; Nijoukubo, D.; Yamakoshi, A.; Peterson, R.E.; Stegeman, J.J.; Kitazawa, T.; Hiraga, T.; Kubota, A. (2014). Involvement of COX2-thromboxane pathway in TCDD-induced precardiac edema in developing zebrafish. Aquat. Toxicol. 154, 19-25.

Tilley SL, Coffman TM, Koller BH. Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes. J Clin Invest. 2001; 108: 15–23.

Vane JR, Mitchell JA, Appleton I, Tomlinson A, Bishop-Bailey D, Croxtall J, Willoughby DA. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci U S A. 1994;91: 2046–2050.

Wong, S.; Fukuchi, M.; Melnyk, P.; Rodger, I.; Giaid, A. (1998). Induction of cyclooxygenase-2 and activation of nuclear factor-kappaB in myocardium of patients with congestive heart failure. Circulation, 98, 100-103.