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

  • ️Warner, Timothy D.
  • ️Sun Jan 01 2006
  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

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

    CAS  PubMed  Google Scholar 

  • 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 

  • 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 

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

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

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

    CAS  PubMed  Google Scholar 

  • 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 

  • 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 

  • 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 

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

    CAS  PubMed  Google Scholar 

  • 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 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

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

    CAS  PubMed  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

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

    CAS  PubMed  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

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

    CAS  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

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

    PubMed  Google Scholar 

  • 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 

  • 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 

  • 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 

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

    PubMed  Google Scholar 

  • 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 

  • 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 

  • 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 

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

    CAS  PubMed  Google Scholar 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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 

  • 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).

  • 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 

  • 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 

  • 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 

  • 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