Roles of Cyclooxygenase (COX)-1 and COX-2 in Prostanoid Production by Human Endothelial Cells: Selective Up-Regulation of Prostacyclin Synthesis by COX-2
Abstract
The two cyclooxygenase (COX) isoforms, COX-1 and COX-2, both metabolize arachidonic acid to PGH2, the common substrate for thromboxane A2 (TXA2), prostacyclin (PGI2), and PGE2 synthesis. We characterized the synthesis of these prostanoids in HUVECs in relation to COX-1 and COX-2 activity. Untreated HUVEC expressed only COX-1, whereas addition of IL-1β caused induction of COX-2. TXA2 was the predominant COX-1-derived product, and TXA2 synthesis changed little with up-regulation of COX-2 by IL-1β (2-fold increase). By contrast, COX-2 up-regulation was associated with large increases in the synthesis of PGI2 and PGE2 (54- and 84-fold increases, respectively). Addition of the selective COX-2 inhibitor, NS-398, almost completely abolished PGI2 and PGE2 synthesis, but had little effect on TXA2 synthesis. The up-regulation of COX-2 by IL-1β was accompanied by specific up-regulation of PGI synthase and PGE synthase, but not TX synthase. An examination of the substrate concentration dependencies showed that the pathway of TXA2 synthesis was saturated at a 20-fold lower arachidonic acid concentration than that for PGI2 and PGE2 synthesis. In conclusion, endothelial prostanoid synthesis appears to be differentially regulated by the induction of COX-2. The apparent PGI2 and PGE2 linkage with COX-2 activity may be explained by a temporal increase in total COX activity, together with selective up-regulation of PGI synthase and PGE synthase, and different kinetic characteristics of the terminal synthases. These findings have particular importance with regard to the potential for cardiovascular consequences of COX-2 inhibition.
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COX utilize lipid substrates, generally arachidonic acid.
“They utilize lipid substrates, generally arachidonic acid, and produce a variety of prostaglandins, lipid oxidation products with important physiological effects (156).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [156]
COX produce a variety of prostaglandins, lipid oxidation products with important physiological effects.
“They utilize lipid substrates, generally arachidonic acid, and produce a variety of prostaglandins, lipid oxidation products with important physiological effects (156).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [156]
COX2 is induced under inflammatory conditions to produce PGE2 and prostacyclin, while COX1 leads to signaling primarily through thromboxane A2.
“Isoforms can also produce different signaling agents as exemplified by the COX enzymes; COX2 is induced under inflammatory conditions to produce PGE2 and prostacyclin (PGI2) while COX1 leads to a signaling cascade primarily through thromboxane A2 (TXA2) [10].”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [10]
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- Authors
- Caughey, G. E., Cleland, L. G., Penglis, P. S., Gamble, J. R., & James, M. J.
- Affiliations
- Royal Adelaide Hospital (AU)
- Hanson Institute (AU)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-09-01
- Volume
- 167
- Issue
- 5
- Pages
- 2831-2838
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1803320375
- Cited by
- 283
- References
- 37
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 10 · 2023: 10 · 2022: 8 · 2021: 9 · 2020: 17 · 2019: 9 · 2018: 20 · 2017: 15 · 2016: 11 · 2015: 12 · 2014: 8 · 2013: 11 · 2012: 6
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- cyclooxygenase-2, cyclooxygenase-1, prostacyclin synthesis, prostaglandin E2 synthesis, thromboxane A2 synthesis, endothelial cells, IL-1β, COX-2 induction, arachidonic acid metabolism, NS-398
- MeSH terms
- Prostaglandin-E Synthases, Aspirin, Cells, Cultured, Cytochrome P-450 Enzyme System, Endothelium, Vascular, Enzyme Induction, Humans, Interleukin-1, Isoenzymes, Kinetics, Membrane Proteins, Prostaglandin-Endoperoxide Synthases, Prostaglandins, Epoprostenol, Thromboxane A2, Thromboxane-A Synthase, Dinoprostone, Up-Regulation, Cyclooxygenase Inhibitors, Intramolecular Oxidoreductases, Mitogen-Activated Protein Kinases, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors
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