Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs

Nature Reviews Drug Discovery volume 5, pages 75–86 (2006)Cite this article

Key Points

  • The formation of prostanoids depends on the function of cyclooxygenase (COX) enzymes that convert, through a two-step process, arachidonic acid into prostaglandin H2, the precursor of the other prostanoids.

  • COX enzymes exist in two forms: COX1, which seems to be more associated with physiological functions, and COX2, which is readily inducible and seems to be more associated with pathological functions. These enzymes are the targets for the non-steroidal anti-inflammatory drugs (NSAIDs). Work in the past 10–15 years has resulted in the production of selective inhibitors of COX2 designed to produce the same anti-inflammatory effects as the traditional NSAIDs, associated with inhibition of COX2, with less damaging effects on the stomach, associated with inhibition of COX1.

  • Following the introduction of selective COX2 inhibitors around 5 years ago there has been much debate as to whether these drugs are actually safer than the traditional NSAIDs they were meant to replace. In particular, it has been proposed that selective inhibition of COX2 is associated with an increased incidence of thrombotic events driven by a reduction in the formation of the antithrombotic prostanoid, prostacylin, in blood vessels. This, it has been suggested, negates any safety benefits in the gastrointestinal tract. In the autumn of 2004, the COX2-selective drug rofecoxib was withdrawn from the market because of an excess of thrombotic events in a placebo-controlled trial investigating its usefulness in the prevention of colon cancer.

  • Discussions have continued, often hampered by the lack of data for traditional NSAIDs from controlled clinical trials. Here we discuss the evidence and the latest recommendations for the use of selective inhibitors of COX2 as well as the traditional NSAIDs.

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of prostanoids by the enzyme cyclooxygenase (COX). Work in the past 15 years has shown that COX exists in two forms: COX1, which is largely associated with physiological functions, and COX2, which is largely associated with pathological functions. Heated debate followed the introduction of selective COX2 inhibitors around 5 years ago: do these drugs offer any advantages over the traditional NSAIDs they were meant to replace, particularly in regard to gastrointestinal and cardiovascular side effects? Here we discuss the evidence and the latest recommendations for the use of selective inhibitors of COX2 as well as the traditional NSAIDs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pathways of prostanoid formation.
Figure 2: Contrasting vascular effects of prostacyclin and thromboxane A2.
Figure 3: Platelet COX1 versus platelet COX2.
Figure 4: COX1 versus COX2 in healthy and inflamed vessels.
Figure 5: Highly selective inhibitors of COX2 have no effect on the production of platelet thromboxane A2 in vivo or in vitro, but may reduce vascular prostacyclin.

Similar content being viewed by others

References

  1. Vane, J. R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol. 231, 232–235 (1971).

    CAS  PubMed  Google Scholar 

  2. Ferreira, S. H., Moncada, S. & Vane, J. R. Indomethacin and aspirin abolish prostaglandin release from the spleen. Nature New Biol. 231, 237–239 (1971).

    CAS  PubMed  Google Scholar 

  3. Smith, J. B. & Willis, A. L. Aspirin selectively inhibits prostaglandin production in human platelets. Nature New Biol. 231, 235–237 (1971). References 1–3 are back-to-back papers establishing that NSAIDs have the common mechanism of action of inhibiting prostanoid formation. Reference 3 in particular showed that aspirin inhibited prostanoid formation in platelets; now known, of course, to be thromboxane A 2.

    CAS  PubMed  Google Scholar 

  4. Vane, J. R., Bakhle, Y. S. & Botting, R. M. Cyclooxygenase 1 and 2. Annu. Rev. Pharmacol. Toxicol. 38, 97–120 (1998).

    CAS  PubMed  Google Scholar 

  5. Smith, W. L., DeWitt, D. L. & Garavito, R. M. Cyclooxygenases: structural, cellular and molecular biology. Annu. Rev. Biochem. 69, 145–182 (2000).

    CAS  PubMed  Google Scholar 

  6. DuBois, R. N. et al. Cyclooxygenase in biology and disease. FASEB J. 12, 1063–1073 (1998).

    CAS  PubMed  Google Scholar 

  7. FitzGerald, G. A. & Patrono, C. The coxibs, selective inhibitors of cyclooxygenase-2. N. Engl. J. Med. 345, 433–442 (2001).

    CAS  PubMed  Google Scholar 

  8. Flower, R. J. The development of COX2 inhibitors. Nature Rev. Drug Discov. 2, 179–191 (2003).

    CAS  Google Scholar 

  9. Warner, T. D. & Mitchell, J. A. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J. 18, 790–804 (2004).

    CAS  PubMed  Google Scholar 

  10. Rosen, G. D., Birkenmeier, T. M., Raz, A. & Holtzman, M. J. Identification of a cyclooxygenase-related gene and its potential role in prostaglandin formation. Biochem. Biophys. Res. Commun. 164, 1358–1365 (1989). Study published 2 years before the publication of definitive characterizations of COX2 showing that cell culture greatly increased the production of prostanoids and that this was associated with the appearance of a COX-related mRNA, suggesting the existence of an inducible isoform of COX.

    CAS  PubMed  Google Scholar 

  11. Xie, W. L., Chipman, J. G., Robertson, D. L., Erikson, R. L. & Simmons, D. L. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc. Natl Acad. Sci. USA 88, 2692–2696 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Kujubu, D. A., Fletcher, B. S., Varnum, B. C., Lim, R. W. & Herschman, H. R. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J. Biol. Chem. 266, 12866–12872 (1991).

    CAS  PubMed  Google Scholar 

  13. Hla, T. & Neilson, K. Human cyclooxygenase-2 cDNA. Proc. Natl Acad. Sci. USA 89, 7384–7388 (1992). References 11–13 report the initial definitive reports of the existence of COX2.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Masferrer, J. L., Seibert, K., Zweifel, B. & Needleman, P. Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme. Proc. Natl Acad. Sci. USA 89, 3917–3921 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. O'Banion, M. K., Winn, V. D. & Young, D. A. cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc. Natl Acad. Sci. USA 89, 4888–4892 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Mitchell, J. A., Akarasereenont, P., Thiemermann, C., Flower, R. J. & Vane, J. R. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc. Natl Acad. Sci. USA 90, 11693–11697 (1993). Early study demonstrating in isolated cell systems, notably including endothelial cells, that NSAIDs show differential selectivity for COX1 and COX2.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Mitchell, J. A. & Evans, T. W. Cyclooxygenase-2 as a therapeutic target. Inflamm. Res. 47 (Suppl. 2), S88–S92 (1998).

    CAS  PubMed  Google Scholar 

  18. McAdam, B. F. et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc. Natl Acad. Sci. USA 96, 272–277 (1999). Clinical study that showed that dosing of healthy volunteers with celecoxib reduced urinary prostacyclin metabolites. Led to the idea that prostacyclin production by endothelial cells within the circulation is dependent on the activity of COX2.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Catella-Lawson, F. et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J. Pharmacol. Exp. Ther. 289, 735–741 (1999).

    CAS  PubMed  Google Scholar 

  20. Fitzgerald, G. A. Coxibs and cardiovascular disease. N. Engl. J. Med. 351, 1709–1711 (2004).

    CAS  PubMed  Google Scholar 

  21. Horton, R. Vioxx, the implosion of Merck, and aftershocks at the FDA. Lancet 364, 1995–1996 (2004).

    PubMed  Google Scholar 

  22. Topol, E. J. Failing the public health — rofecoxib, Merck, and the FDA. N. Engl. J. Med. 351, 1707–1709 (2004).

    CAS  PubMed  Google Scholar 

  23. Okie, S. Raising the safety bar — the FDA's coxib meeting. N. Engl. J. Med. 352, 1283–1285 (2005).

    CAS  PubMed  Google Scholar 

  24. Antman, E. M., DeMets, D. & Loscalzo, J. Cyclooxygenase inhibition and cardiovascular risk. Circulation 112, 759–770 (2005).

    CAS  PubMed  Google Scholar 

  25. Chandrasekharan, N. V. et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc. Natl Acad. Sci. USA 99, 13926–13931 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Simmons, D. L., Botting, R. M. & Hla, T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol. Rev. 56, 387–437 (2004).

    CAS  PubMed  Google Scholar 

  27. Schade, S. et al. Diverse functional coupling of cyclooxygenase 1 and 2 with final prostanoid synthases in liver macrophages. Biochem. Pharmacol. 64, 1227–1232 (2002).

    CAS  PubMed  Google Scholar 

  28. Snipes, J. A., Kis, B., Shelness, G. S., Hewett, J. A. & Busija, D. W. Cloning and characterization of cyclooxygenase-1b (putative COX-3) in rat. J. Pharmacol. Exp. Ther. 313, 668–676 (2005).

    CAS  PubMed  Google Scholar 

  29. Warner, T. D. & Mitchell, J. A. Cyclooxygenase-3 (COX-3): filling in the gaps toward a COX continuum? Proc. Natl Acad. Sci. USA 99, 13371–13373 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Warner, T. D. et al. Cyclooxygenases 1, 2, and 3 and the production of prostaglandin I2: investigating the activities of acetaminophen and cyclooxygenase-2-selective inhibitors in rat tissues. J. Pharmacol. Exp. Ther. 310, 642–647 (2004).

    CAS  PubMed  Google Scholar 

  31. Kis, B., Snipes, J. A. & Busija, D. W. Acetaminophen and the COX-3 puzzle: sorting out facts, fictions and uncertainties. J. Pharmacol. Exp. Ther. 315, 1–7 (2005).

    CAS  PubMed  Google Scholar 

  32. Warner, T. D. et al. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc. Natl Acad. Sci. USA 96, 7563–7568 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Mitchell, J. A. & Warner, T. D. Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy. Br. J. Pharmacol. 128, 1121–1132 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Perini, R., Fiorucci, S. & Wallace, J. L. Mechanisms of nonsteroidal anti-inflammatory drug-induced gastrointestinal injury and repair: a window of opportunity for cyclooxygenase-inhibiting nitric oxide donors. Can. J. Gastroenterol. 18, 229–236 (2004).

    PubMed  Google Scholar 

  35. Zimmermann, K. C., Sarbia, M., Schror, K. & Weber, A. A. Constitutive cyclooxygenase-2 expression in healthy human and rabbit gastric mucosa. Mol. Pharmacol. 54, 536–540 (1998).

    CAS  PubMed  Google Scholar 

  36. Wallace, J. L., McKnight, W., Reuter, B. K. & Vergnolle, N. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 119, 706–714 (2000).

    CAS  PubMed  Google Scholar 

  37. Tanaka, A., Hase, S., Miyazawa, T., Ohno, R. & Takeuchi, K. Role of cyclooxygenase (COX)-1 and COX-2 inhibition in nonsteroidal anti-inflammatory drug-induced intestinal damage in rats: relation to various pathogenic events. J. Pharmacol. Exp. Ther. 303, 1248–1254 (2002).

    CAS  PubMed  Google Scholar 

  38. Langenbach, R. et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 83, 483–492 (1995).

    CAS  PubMed  Google Scholar 

  39. Sigthorsson, G. et al. COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice. Gastroenterology 122, 1913–1923 (2002).

    CAS  PubMed  Google Scholar 

  40. Vane, J. R. & Warner, T. D. Nomenclature for COX-2 inhibitors. Lancet 356, 1373–1374 (2000).

    CAS  PubMed  Google Scholar 

  41. Moncada, S., Gryglewski, R., Bunting, S. & Vane, J. R. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263, 663–665 (1976). First description of prostacyclin and demonstration of its capacity to inhibit platelet aggregation.

    CAS  PubMed  Google Scholar 

  42. Hamberg, M., Svensson, J. & Samuelsson, B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc. Natl Acad. Sci. USA 72, 2994–2998 (1975). First definitive characterization of the thromboxanes; formed by platelets, thromboxane A 2 drives the formation of thrombi and is the therapeutic target of low-dose aspirin.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Roth, G. J., Machuga, E. T. & Ozols, J. Isolation and covalent structure of the aspirin-modified, active-site region of prostaglandin synthetase. Biochemistry 22, 4672–4675 (1983).

    CAS  PubMed  Google Scholar 

  44. Patrono, C. Aspirin: new cardiovascular uses for an old drug. Am. J. Med. 110, 62S–65S (2001).

    CAS  PubMed  Google Scholar 

  45. Pedersen, A. K. & FitzGerald, G. A. Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase. N. Engl. J. Med. 311, 1206–1211 (1984).

    CAS  PubMed  Google Scholar 

  46. Murata, T. et al. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 388, 678–682 (1997).

    CAS  PubMed  Google Scholar 

  47. Cheng, Y. et al. Role of prostacyclin in the cardiovascular response to thromboxane A2 . Science 296, 539–541 (2002).

    CAS  PubMed  Google Scholar 

  48. Rocca, B. et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc. Natl Acad. Sci. USA 99, 7634–7639 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Tanaka, N., Sato, T., Fujita, H. & Morita, I. Constitutive expression and involvement of cyclooxygenase-2 in human megakaryocytopoiesis. Arterioscler. Thromb. Vasc. Biol. 24, 607–612 (2004).

    CAS  PubMed  Google Scholar 

  50. Hasan, K., Warner, T. D., Vojnovic, I., Pepper, J. R. & Mitchell. Characterisation of cyclo-oxygenase activity in human megakaryocytes: relevance to platelet COX-2. British Pharmacological Society Meeting, London, UK, December, pA2 online. 2004;4:036P (2003).

    Google Scholar 

  51. Weber, A. A. et al. Flow cytometry analysis of platelet cyclooxygenase-2 expression: induction of platelet cyclooxygenase-2 in patients undergoing coronary artery bypass grafting. Br. J. Haematol. 117, 424–426 (2002).

    CAS  PubMed  Google Scholar 

  52. Censarek, P. et al. Cyclooxygenase COX-2a, a novel COX-2 mRNA variant, in platelets from patients after coronary artery bypass grafting. Thromb. Haemost. 92, 925–928 (2004).

    CAS  PubMed  Google Scholar 

  53. Patrignani, P. Aspirin insensitive eicosanoid biosynthesis in cardiovascular disease. Thromb. Res. 110, 281–286 (2003).

    CAS  PubMed  Google Scholar 

  54. Sanderson, S., Emery, J., Baglin, T. & Kinmonth, A. L. Narrative review: aspirin resistance and its clinical implications. Ann. Intern. Med. 142, 370–380 (2005).

    CAS  PubMed  Google Scholar 

  55. Belton, O., Byrne, D., Kearney, D., Leahy, A. & Fitzgerald, D. J. Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation 102, 840–845 (2000).

    CAS  PubMed  Google Scholar 

  56. Bishop-Bailey, D. et al. Induction of cyclooxygenase-2 in human saphenous vein and internal mammary artery. Arterioscler. Thromb. Vasc. Biol. 17, 1644–1648 (1997).

    CAS  PubMed  Google Scholar 

  57. Bishop-Bailey, D., Pepper, J. R., Larkin, S. W. & Mitchell, J. A. Differential induction of cyclo-oxygenase-2 in human arterial and venous smooth muscle: role of endogenous prostanoids. Arterioscler. Thromb. Vasc. Biol. 18, 1655–1661 (1998).

    CAS  PubMed  Google Scholar 

  58. Jimenez, R. et al. Role of Toll-like receptors 2 and 4 in the induction of cyclooxygenase-2 in vascular smooth muscle. Proc. Natl Acad. Sci. USA 102, 4637–4462 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Topper, J. N., Cai, J., Falb, D. & Gimbrone, M. A. Jr. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc. Natl Acad. Sci. USA 93, 10417–10422 (1996). Paper demonstrating that COX2 expression can be increased in endothelial cells in culture by short-term exposure to shear forces. Taken as support of the hypothesis that endothelial cells normally express COX2 within blood vessels.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Inoue, H. et al. Transcriptional and posttranscriptional regulation of cyclooxygenase-2 expression by fluid shear stress in vascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 22, 1415–1420 (2002).

    CAS  PubMed  Google Scholar 

  61. Doroudi, R., Gan, L. M., Selin Sjogren, L. & Jern, S. Effects of shear stress on eicosanoid gene expression and metabolite production in vascular endothelium as studied in a novel biomechanical perfusion model. Biochem. Biophys. Res. Commun. 269, 257–264 (2000).

    CAS  PubMed  Google Scholar 

  62. McCormick, S. M., Whitson, P. A., Wu, K. K. & McIntire, L. V. Shear stress differentially regulates PGHS-1 and PGHS-2 protein levels in human endothelial cells. Ann. Biomed. Eng. 28, 824–833 (2000).

    CAS  PubMed  Google Scholar 

  63. Dancu, M. B., Berardi, D. E., Vanden Heuvel, J. P. & Tarbell, J. M. Asynchronous shear stress and circumferential strain reduces endothelial NO synthase and cyclooxygenase-2 but induces endothelin-1 gene expression in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 24, 2088–2094 (2004).

    CAS  PubMed  Google Scholar 

  64. Okahara, K., Sun, B. & Kambayashi, J. Upregulation of prostacyclin synthesis-related gene expression by shear stress in vascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 18, 1922–1926 (1998).

    CAS  PubMed  Google Scholar 

  65. Wasserman, S. M. et al. Gene expression profile of human endothelial cells exposed to sustained fluid shear stress. Physiol. Genomics 12, 13–23 (2002).

    CAS  PubMed  Google Scholar 

  66. McCormick, S. M. et al. DNA microarray reveals changes in gene expression of shear stressed human umbilical vein endothelial cells. Proc. Natl Acad. Sci. USA 98, 8955–8960 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Warabi, E. et al. Effect on endothelial cell gene expression of shear stress, oxygen concentration, and low-density lipoprotein as studied by a novel flow cell culture system. Free Radic. Biol. Med. 37, 682–694 (2004).

    CAS  PubMed  Google Scholar 

  68. Chen, B. P. et al. DNA microarray analysis of gene expression in endothelial cells in response to 24-h shear stress. Physiol. Genomics 7, 55–63 (2001).

    CAS  PubMed  Google Scholar 

  69. Garcia-Cardena, G., Comander, J., Anderson, K. R., Blackman, B. R. & Gimbrone, M. A. Jr. Biomechanical activation of vascular endothelium as a determinant of its functional phenotype. Proc. Natl Acad. Sci. USA 98, 4478–4485 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ohura, N. et al. Global analysis of shear stress-responsive genes in vascular endothelial cells. J. Atheroscler. Thromb. 10, 304–313 (2003).

    CAS  PubMed  Google Scholar 

  71. Dai, G. et al. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. Proc. Natl Acad. Sci. USA 101, 14871–14876 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Brooks, A. R., Lelkes, P. I. & Rubanyi, G. M. Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow. Physiol. Genomics 9, 27–41 (2002).

    CAS  PubMed  Google Scholar 

  73. Yoshisue, H. et al. Large scale isolation of non-uniform shear stress-responsive genes from cultured human endothelial cells through the preparation of a subtracted cDNA library. Atherosclerosis 162, 323–334 (2002).

    CAS  PubMed  Google Scholar 

  74. Resnick, N. & Gimbrone, M. A. Jr. Hemodynamic forces are complex regulators of endothelial gene expression. FASEB J. 9, 874–882 (1995).

    CAS  PubMed  Google Scholar 

  75. Dekker, R. J. et al. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Kruppel-like factor (KLF2). Blood 100, 1689–1698 (2002).

    CAS  PubMed  Google Scholar 

  76. Baker, C. S. et al. Cyclooxygenase-2 is widely expressed in atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages. Arterioscler. Thromb. Vasc. Biol. 19, 646–655 (1999).

    CAS  PubMed  Google Scholar 

  77. Schonbeck, U., Sukhova, G. K., Graber, P., Coulter, S. & Libby, P. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am. J. Pathol. 155, 1281–1291 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Stemme, V., Swedenborg, J., Claesson, H. & Hansson, G. K. Expression of cyclo-oxygenase-2 in human atherosclerotic carotid arteries. Eur. J. Vasc. Endovasc. Surg. 20, 146–152 (2000).

    CAS  PubMed  Google Scholar 

  79. Lucas, R. et al. Expression of COX-1, but not COX-2 or COX-3; like immunoreactivity in human blood vessels and heart. British Pharmacological Society Meeting, London, UK, December, pA2online 2004;1(4):035P (2003).

    Google Scholar 

  80. Hamilton, L. C., Mitchell, J. A., Tomlinson, A. M. & Warner, T. D. Synergy between cyclo-oxygenase-2 induction and arachidonic acid supply in vivo: consequences for nonsteroidal anti-inflammatory drug efficacy. FASEB J. 13, 245–251 (1999).

    CAS  PubMed  Google Scholar 

  81. Pratico, D., Tillmann, C., Zhang, Z. B., Li, H. & FitzGerald, G. A. Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice. Proc. Natl Acad. Sci. USA 98, 3358–3363 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Csiszar, A. et al. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ. Res. 90, 1159–1166 (2002).

    CAS  PubMed  Google Scholar 

  83. Wong, E., Huang, J. Q., Tagari, P. & Riendeau, D. Effects of COX-2 inhibitors on aortic prostacyclin production in cholesterol-fed rabbits. Atherosclerosis 157, 393–402 (2001).

    CAS  PubMed  Google Scholar 

  84. Rudic, R. D. et al. COX-2-derived prostacyclin modulates vascular remodeling. Circ. Res. 96, 1240–1247 (2005).

    CAS  PubMed  Google Scholar 

  85. Riendeau, D. et al. Comparison of the cyclo-oxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can. J. Physiol. Pharmacol. 75, 1088–1095 (1997).

    CAS  PubMed  Google Scholar 

  86. Boutaud, O., Aronoff, D. M., Richardson, J. H., Marnett, L. J. & Oates, J. A. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H2 synthases. Proc. Natl Acad. Sci. USA 99, 7130–7135 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Aronoff, D. M., Boutaud, O., Marnett, L. J. & Oates, J. A. Inhibition of prostaglandin H2 synthases by salicylate is dependent on the oxidative state of the enzymes. J. Pharmacol. Exp. Ther. 304, 589–595 (2003).

    CAS  PubMed  Google Scholar 

  88. Lucas, R., Warner, T. D., Vojnovic, I. & Mitchell, J. A. Cellular mechanisms of acetaminophen: role of cyclo-oxygenase. FASEB J. 19, 635–637 (2005).

    CAS  PubMed  Google Scholar 

  89. Harris, R. C. et al. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J. Clin. Invest. 94, 2504–2510 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Athirakul, K., Kim, H. S., Audoly, L. P., Smithies, O. & Coffman, T. M. Deficiency of COX-1 causes natriuresis and enhanced sensitivity to ACE inhibition. Kidney Int. 60, 2324–2329 (2001).

    CAS  PubMed  Google Scholar 

  91. Epstein, M. Non-steroidal anti-inflammatory drugs and the continuum of renal dysfunction. J. Hypertens. 20 (Suppl. 6), S17–S23 (2002).

    CAS  Google Scholar 

  92. Whelton, A. COX-2-specific inhibitors and the kidney: effect on hypertension and oedema. J. Hypertens. 20 (Suppl. 6), S31–S35 (2002).

    CAS  Google Scholar 

  93. Therland, K. L. et al. Cycloxygenase-2 is expressed in vasculature of normal and ischemic adult human kidney and is colocalized with vascular prostaglandin E2 EP4 receptors. J. Am. Soc. Nephrol. 15, 1189–1198 (2004).

    CAS  PubMed  Google Scholar 

  94. Singh, G. et al. Consequences of increased systolic blood pressure in patients with osteoarthritis and rheumatoid arthritis. J. Rheumatol. 30, 714–719 (2003).

    PubMed  Google Scholar 

  95. Dilger, K. et al. Effects of celecoxib and diclofenac on blood pressure, renal function, and vasoactive prostanoids in young and elderly subjects. J. Clin. Pharmacol. 42, 985–994 (2002).

    CAS  PubMed  Google Scholar 

  96. Schwartz, J. I. et al. Cyclooxygenase-2 inhibition by rofecoxib reverses naturally occurring fever in humans. Clin. Pharmacol. Ther. 65, 653–660 (1999).

    CAS  PubMed  Google Scholar 

  97. Rossat, J., Maillard, M., Nussberger, J., Brunner, H. R. & Burnier, M. Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin. Pharmacol. Ther. 66, 76–84 (1999).

    CAS  PubMed  Google Scholar 

  98. Patrignani, P., Capone, M. L. & Tacconelli, S. Clinical pharmacology of etoricoxib: a novel selective COX-2 inhibitor. Expert Opin. Pharmacother. 4, 265–284 (2003).

    CAS  PubMed  Google Scholar 

  99. Alsalameh, S., Burian, M., Mahr, G., Woodcock, B. G. & Geisslinger, G. The pharmacological properties and clinical use of valdecoxib, a new cyclo-oxygenase-2-selective inhibitor. Aliment. Pharmacol. Ther. 17, 489–501 (2003).

    CAS  PubMed  Google Scholar 

  100. Zewde, T. & Mattson, D. L. Inhibition of cyclooxygenase-2 in the rat renal medulla leads to sodium-sensitive hypertension. Hypertension 44, 424–428 (2004).

    CAS  PubMed  Google Scholar 

  101. Whelton, A. et al. Effects of celecoxib and naproxen on renal function in the elderly. Arch. Intern. Med. 160, 1465–1470 (2000).

    CAS  PubMed  Google Scholar 

  102. Swan, S. K. et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann. Intern. Med. 133, 1–9 (2000).

    CAS  PubMed  Google Scholar 

  103. Whelton, A. et al. SUCCESS VI Study Group. Cyclooxygenase-2-specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am. J. Ther. 8, 85–95 (2001).

    CAS  PubMed  Google Scholar 

  104. Whelton, A. et al. Effects of celecoxib and rofecoxib on blood pressure and edema in patients ≥65 years of age with systemic hypertension and osteoarthritis. Am. J. Cardiol. 90, 959–963 (2002).

    CAS  PubMed  Google Scholar 

  105. Mamdani, M. et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 363, 1751–1756 (2004).

    CAS  PubMed  Google Scholar 

  106. Farkouh, M. E. et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 364, 675–684 (2004).

    CAS  PubMed  Google Scholar 

  107. Day, R. Hypertension in the patient with arthritis: have we been underestimating its significance? J. Rheumatol. 30, 642–645 (2003).

    PubMed  Google Scholar 

  108. Bombardier, C. et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N. Engl. J. Med. 343, 1520–1528 (2000). One of the first two large-scale clinical trials of a COX2-selective drug versus a traditional NSAID. This study generated great interest because although it showed reduced serious adverse gastrointestinal events for rofecoxib compared with naproxen it also showed increased thrombotic events.

    CAS  PubMed  Google Scholar 

  109. Silverstein, F. E. et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 284, 1247–1255 (2000). One of the first two large-scale clinical trials of a COX2-selective drug versus a traditional NSAID. Sparked some controversy because analysis of the full data set showed that although celecoxib produced fewer gastrointestinal adverse events than ibuprofen it was not different to diclofenac at any time point, even taking into account the consumption of aspirin.

    CAS  PubMed  Google Scholar 

  110. Schnitzer, T. J. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 364, 665–674 (2004).

    CAS  PubMed  Google Scholar 

  111. Topol, E. J. & Falk, G. W. A coxib a day won't keep the doctor away. Lancet 364, 639–640 (2004).

    PubMed  Google Scholar 

  112. Kaufman, D. W., Kelly, J. P., Rosenberg, L., Anderson, T. E. & Mitchell, A. A. Are cyclooxygenase-2 inhibitors being taken only by those who need them? Arch. Intern. Med. 165, 1066–1067 (2005).

    PubMed  Google Scholar 

  113. Graham, D. J. et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 365, 475–481 (2005).

    CAS  PubMed  Google Scholar 

  114. Solomon, D. H. et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 109, 2068–2073 (2004).

    CAS  PubMed  Google Scholar 

  115. Juni, P. et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 364, 2021–2029 (2004).

    CAS  PubMed  Google Scholar 

  116. Bresalier, R. S. et al. Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N. Engl. J. Med. 352, 1092–1102 (2005). Controlled trial of rofecoxib versus placebo, data from which precipitated the withdrawal of rofecoxib from the market.

    CAS  PubMed  Google Scholar 

  117. Solomon, S. D. et al. Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl J Med. 352, 1071–1080 (2005).

    CAS  PubMed  Google Scholar 

  118. Ott, E. et al. Efficacy and safety of the cyclo-oxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J. Thorac. Cardiovasc. Surg. 125, 1481–1492 (2003).

    CAS  PubMed  Google Scholar 

  119. Nussmeier, N. A. et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N. Engl. J. Med. 352, 1081–1091 (2005).

    CAS  PubMed  Google Scholar 

  120. Reilly, I. A. & FitzGerald, G. A. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 69, 180–186 (1987).

    CAS  PubMed  Google Scholar 

  121. Capone, M. L. et al. Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation 109, 1468–1471 (2004).

    CAS  PubMed  Google Scholar 

  122. Shaya, F. T., Blume, S. W., Blanchette, C. M., Weir, M. R. & Mullins, C. D. Selective cyclooxygenase-2 inhibition and cardiovascular effects: an observational study of a Medicaid population. Arch. Intern. Med. 165, 181–186 (2005).

    CAS  PubMed  Google Scholar 

  123. Johnsen, S. P. et al. Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study. Arch. Intern. Med. 165, 978–984 (2005).

    CAS  PubMed  Google Scholar 

  124. Singh, G., Mithal, A. & Triadafilopoulos, G. Both selective COX-2 inhibitors and nonselective NSAIDs increase the risk of acute myocardial infarction in patients with arthritis: selectivity is with the patient, not the drug class. Annu. Eur. Congress Rheumatol. Vienna, Austria, 8–11 June, Abstract OP0091 (2005).

  125. Roth, S. H. Nonsteroidal antiinflammatory drug gastropathy: we started it, why don't we stop it? J. Rheumatol. 32, 1189–1191 (2005).

    PubMed  Google Scholar 

  126. Olsen, N. J. Tailoring arthritis therapy in the wake of the NSAID crisis. N. Engl. J. Med. 352, 2578–2580 (2005).

    CAS  PubMed  Google Scholar 

  127. Fischer, L. M., Schlienger, R. G., Matter, C. M., Jick, H. & Meier, C. R. Discontinuation of nonsteroidal anti-inflammatory drug therapy and risk of acute myocardial infarction. Arch. Intern. Med. 164, 2472–2476 (2004).

    CAS  PubMed  Google Scholar 

  128. McKeever, T. M. et al. The association of acetaminophen, aspirin, and ibuprofen with respiratory disease and lung function. Am. J. Respir. Crit. Care Med. 171, 966–971 (2005).

    PubMed  Google Scholar 

Download references

Acknowledgements

Research in T.D.W.'s laboratory is supported by the William Harvey Research Foundation and the European Community FP6 funding.

Author information

Authors and Affiliations

  1. Cardiothoracic Pharmacology, Unit of Critical Care Medicine, National Heart and Lung Institute, Royal Brompton Hospital, Imperial College School of Medicine, Dovehouse Street, London, SW3 6LY, UK

    Jane A. Mitchell

  2. The William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK

    Timothy D. Warner

Authors
  1. Jane A. Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timothy D. Warner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jane A. Mitchell or Timothy D. Warner.

Ethics declarations

Competing interests

J.A.M. has received consulting and/or research support from Novartis and GlaxoSmithKline. T.D.W. has received research support from AAi Pharma and Boehringer Ingelheim, and lecturing and/or consulting fees from AAi Pharma, Boehringer Ingelheim, Merck Inc., Novopharm, Pfizer and Shire Pharmaceuticals.

Related links

Related links

FURTHER INFORMATION

FDA Memo

FDA Advisory Committee Briefing Document

Glossary

Isoforms

Two or more proteins having the same functions and similar (or identical) sequences that are derived from different genes.

Peroxisome proliferator-activated receptors

(PPARs). A family of three nuclear receptors/transcription factors that heterodimerize with retinoid X receptors (RXR). When combined as a PPAR–RXR heterodimer, PPAR ligands and RXR ligands induce gene transcription, with selectivity being introduced through subtle differences in the 'response element' promoter regions they bind.

Prostaglandin endoperoxides

PGG2 and PGH2, the first two prostanoids formed sequentially from arachidonic acid by the action of the two enzymatic sites present on COX enzymes.

Relative risk

Odds of an event happening in one population relative to another. In clinical trials, often the relative risk of an adverse event happening in the test drug group is relative to a control (drug or placebo), taking the risk in the control group to be 1. Relative risk greater than 1 therefore indicates an increased risk of an event compared with control.

Non-adjudicated investigator-reported

Events in a clinical trial that are reported back by the local physician (or other professional) studying the particular trial individual that are not subsequently rechecked (adjudicated) by a central review panel.

Hazard ratio

Similar to relative risk. The chance of an adverse event happening in a test population compared with a control population. A hazard ratio of 2 would indicate a doubling of the chance of experiencing an adverse event.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mitchell, J., Warner, T. COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs. Nat Rev Drug Discov 5, 75–86 (2006). https://doi.org/10.1038/nrd1929

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1929

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing