Key Event Title
|Level of Biological Organization|
Key Event Components
|gene expression||prostaglandin G/H synthase 2||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|AhR mediated mortality, via COX-2||KeyEvent|
|Danio rerio||Danio rerio||High||NCBI|
|Oryzias latipes||Oryzias latipes||High||NCBI|
|Gallus gallus||Gallus gallus||High||NCBI|
Key Event Description
- Prostaglandin-endoperoxide synthase (PTGS; KEGG ID E.C. 22.214.171.124) 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
- 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
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).
Evidence for Perturbation by Stressor
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.