COX-2 in Cardiovascular Disease

Abstract

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 26, No. 5COX-2 in Cardiovascular Disease Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCOX-2 in Cardiovascular Disease David Bishop-Bailey, Jane A. Mitchell and Timothy D. Warner David Bishop-BaileyDavid Bishop-Bailey From Cardiac, Vascular, & Inflammation Research (D.B.-B., T.D.W.), William Harvey Research Institute, Queen Mary University of London; and Cardiothoracic Pharmacology (J.A.M.), Unit of Critical Care Medicine, National Heart and Lung Institute, Royal Brompton Hospital, Imperial College School of Medicine, London, UK. Search for more papers by this author , Jane A. MitchellJane A. Mitchell From Cardiac, Vascular, & Inflammation Research (D.B.-B., T.D.W.), William Harvey Research Institute, Queen Mary University of London; and Cardiothoracic Pharmacology (J.A.M.), Unit of Critical Care Medicine, National Heart and Lung Institute, Royal Brompton Hospital, Imperial College School of Medicine, London, UK. Search for more papers by this author and Timothy D. WarnerTimothy D. Warner From Cardiac, Vascular, & Inflammation Research (D.B.-B., T.D.W.), William Harvey Research Institute, Queen Mary University of London; and Cardiothoracic Pharmacology (J.A.M.), Unit of Critical Care Medicine, National Heart and Lung Institute, Royal Brompton Hospital, Imperial College School of Medicine, London, UK. Search for more papers by this author Originally published1 May 2006https://doi.org/10.1161/01.ATV.0000219672.68024.bcArteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:956–958Prostanoids are a large family of lipid mediators derived from the arachidonic acid metabolites of the cyclooxygenase (COX) enzymes. Therapeutically, COX is the target of the nonsteroid antiinflammatory drugs (NSAIDs), a chemically diverse group that includes ibuprofen, naproxen, and diclofenac, among dozens of others. Inhibition of prostanoid production by traditional NSAIDs accounts for all their major therapeutic effects, such as the dampening down of inflammation and the reduction of fever, and their potentially severe adverse side effects, most commonly within the gastrointestinal tract.1,2See page 1137Since the early 1990’s it has been clear there are two distinct enzymes responsible for the production of prostanoids: a constitutive COX-1 found in all tissues and an inflammation-associated enzyme COX-2.1,2 COX-2 is constitutively expressed in only a few sites, such as parts of the kidney and central nervous system, but is highly upregulated and active at sites of inflammation. These findings led to the hypothesis that selective COX-2 inhibitors could be antiinflammatory without the major side effects associated with traditional NSAIDs. Against this background several COX-2–selective inhibitors have been produced and brought to market, the first two being celecoxib (Celebrex) and rofecoxib (Vioxx).Preclinical studies of these COX-2–selective inhibitors were extremely promising. In animal models, for example, they were demonstrated to be as efficacious as traditional NSAIDs but to be lacking their toxic actions on the gastrointestinal tract. Clinical trials have, however, been marred by controversy. The CLASS trial for celecoxib, a 12-month osteoarthritis study of celecoxib, demonstrated celecoxib to have improved safety relative to ibuprofen but not diclofenac at 6 months, but this advantage was absent at 12 months.1–3 Subsequently, however, a shorter 12-week study, SUCCESS-I, has demonstrated celecoxib to have reduced gastrointestinal toxicity compared with naproxen and diclofenac.4 However, the major controversy surrounding the COX-2–selective drugs arose as a consequence of the VIGOR study comparing rofecoxib to naproxen in patients experiencing rheumatoid arthritis.5 Although data from the VIGOR study clearly demonstrated that rofecoxib produced fewer severe adverse events in the gastrointestinal tract than naproxen, it also indicated that significantly more thrombotic events, notably myocardial infarctions, occurred in those taking rofecoxib than in those taking naproxen.1,2,5 More recently data from a placebo-controlled trial for rofecoxib in the prevention of colon cancer recurrence also suggested an excess of thrombotic events after long term, >18 months consumption of rofecoxib, and the drug was withdrawn by the manufacturer.6 Because of the very large scale consumption of NSAIDs and COX-2–selective drugs and the accordingly large potential risk to public health the cardiovascular side effects of COX-2 inhibitors have been under scrutiny over these last few years. Much current evidence suggests that COX-2–selective inhibitors, traditional NSAIDs, and acetaminophen (which also inhibits COX) may all increase the risk of thrombotic events, particularly when taken at high doses for prolonged periods of times.1,2,7The mechanism, or mechanisms, underlying the increase in thrombotic events associated with the NSAIDs is unclear. One explanation may be found in the observation that COX-2–selective drugs and traditional NSAIDs reduce the body’s production of prostaglandin (PG) I2.8,9 PGI2 is a local hormone that reduces platelet reactivity and increases bleeding time so inhibition of its production could well increase the risk of thrombosis.1,2The fact that COX-2–selective inhibitors reduce circulating PGI2 levels is intriguing, as although healthy blood vessels are known to contain abundant amounts of both COX-1 and PGI synthase there is little evidence for COX-2.2,10 In contrast, COX-2 is present after vascular damage, and is highly expressed in atherosclerotic lesions and aortic aneurysms in animal models and human tissue.1,2,11–17 PGI2 is generally protective within the vasculature irrespective of whether it derives from COX-1 or COX-2. It is easy therefore to conceive that as a response to injury COX-2 is induced in the vessel to produce protective vascular PGI2.18 But circumstances may be different in highly inflamed or diseased vessels in which COX-2 is highly expressed and potentially producing large amounts of alternative prostanoids, eg, endoperoxides and PGE2. PGE2 can promote the expression of matrix metalloproteinases and the cell death associated with tissue destruction and vascular lesion instability.16,19 The roles of COX-2 in inflamed or highly diseased vascular lesions are far from clear, though some limited clinical evidence suggests that COX-2, rather than being protective, produces prostanoids with detrimental actions. PGE synthase, for example, is particularly localized in unstable atherosclerotic plaques.19 Interestingly, in patients with acute coronary syndromes dosing with the COX-2–selective drug meloxicam, in conjunction with heparin and aspirin, caused a significant reduction in adverse outcomes.20 Furthermore, NSAID use is associated with a reduction in abdominal aortic aneurysm expansion.16,17In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, King et al21 investigate the roles of COX-1 and COX-2 in a model of abdominal aortic aneurysm. Abdominal aortic aneurysms are caused by local permanent dilation, leading to tissue remodelling, weakening, and the potential of rupture. In man, abdominal aortic aneurysms demonstrate pronounced local inflammation and contain high levels of COX-2, PGE2, and proteolytic enzymes. Using a murine model of angiotensin II-induced abdominal aortic aneurysm, King et al21 show that selective inhibition of COX-2 with oral dosing of celecoxib dramatically reduced the incidence (control, 74%; celecoxib-treated, 11%) and severity of abdominal aortic aneurysms in apoE−/− knockout mice. Inhibition of COX-1 using the COX-1–selective inhibitor SC560 was without effect. Similar results were also observed in the aneurysm-susceptible C57/129 nonhyperlipidemic mouse strain. COX-2 was induced in aneurysm tissue, particularly in vascular smooth muscle cells, and ex vivo PGE2 synthesis was selectively upregulated in aneurysm tissue by exposure to angiotensin II. The reduction in incidence and severity of aneurysms associated with celecoxib appears attributable to local inhibition of COX-2 in the vasculature tissue, as celecoxib affected neither elevations in blood pressure induced by angiotensin II nor circulating total cholesterol levels.The role of COX enzymes in chronic inflammatory vascular lesions clearly needs more investigation. COX enzymes are often described as isolated entities, when in reality their functions are controlled by their environment, the level of substrate available, the expression of individual prostanoid synthase enzymes, and the expression and cellular targets of the prostanoid receptors which mediate their actions. The findings of King et al21 together with others1,2,11–17 indicate that vascular COX enzymes have multiple and varying roles depending on vascular location and environment. Immunohistochemical analyses of large blood vessels shows us that in healthy states COX-1 produces protective PGI2 constitutively. As an acute response to change or injury protective PGI2 may also come from induced COX-2. However, in complex chronic inflammatory lesions the environment changes, and COX-2 is expressed at high levels that may lead to the production of deleteriously large amounts of PGE2 and alternative prostanoids (see the Figure). Within an individual’s vascular tree, under dynamic conditions, all such circumstances could conceivably apply at the same time, with different COX isoforms associated with the production of both protective and deleterious prostanoids at different sites. Download figureDownload PowerPointPotential roles of COX enzymes in large vessel vascular disease. Top panel, The healthy vessel. COX-1 is expressed in the endothelium producing protective PGI2. PGI synthase (PGIS) is expressed in both the endothelium and vascular smooth muscle. Middle panel, The acute response stress or injury. Along with endothelial COX-1, COX-2 is induced in the endothelium and underlying vascular smooth muscle to produce protective PGI2 from the constitutively expressed PGIS. Lower panel, The chronic inflammatory vascular lesion. COX-2 along with PGE synthase is induced in macrophages and vascular smooth muscle producing large amounts of deleterious PGE2, which in turn induces tissue destructive metalloproteinases (MMPs) and cell death.FootnotesCorrespondence to Dr David Bishop-Bailey, Cardiac, Vascular, & Inflammation Research, William Harvey Research Institute, Queen Mary University of London, Charterhouse Sq, London, EC1M 6BQ UK. E-mail [email protected] References 1 Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006; 116: 4–15.CrossrefMedlineGoogle Scholar2 Mitchell JA, Warner TD. COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs. Nat Rev Drug Discov. 2006; 5: 75–86.CrossrefMedlineGoogle Scholar3 Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. 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. J Am Med Assoc. 2000; 284: 1247–1255.CrossrefMedlineGoogle Scholar4 Singh G, Fort JG, Goldstein JL, Levy RA, Hanrahan PS, Bello AE, Andrade-Ortega L, Wallemark C, Agrawal NM, Eisen GM, Stenson WF, Triadafilopoulos G; SUCCESS-I Investigators. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med. 2006; 119: 255–266.CrossrefMedlineGoogle Scholar5 Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000; 343: 1520–1528.CrossrefMedlineGoogle Scholar6 Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA; Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005; 352: 1092–1102.CrossrefMedlineGoogle Scholar7 Topol EJ, Falk GW. A coxib a day won’t keep the doctor away. Lancet. 2004; 364: 639–640.CrossrefMedlineGoogle Scholar8 Catella-Lawson F, McAdam B, Morrison BW, Kapoor S, Kujubu D, Antes L, Lasseter KC, Quan H, Gertz BJ, FitzGerald GA. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther. 1999; 289: 735–741.MedlineGoogle Scholar9 McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999; 96: 272–277.CrossrefMedlineGoogle Scholar10 Bishop-Bailey D, Pepper JR, Haddad EB, Newton R, Larkin SW, Mitchell JA. Induction of cyclooxygenase-2 in human saphenous vein and internal mammary artery. Arterioscler Thromb Vasc Biol. 1997; 17: 1644–1648.CrossrefMedlineGoogle Scholar11 Baker CS, Hall RJ, Evans TJ, Pomerance A, Maclouf J, Creminon C, Yacoub MH, Polak JM. 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. 1999; 19: 646–655.CrossrefMedlineGoogle Scholar12 Belton OA, Duffy A, Toomey S, Fitzgerald DJ. Cyclooxygenase isoforms and platelet vessel wall interactions in the apolipoprotein E knockout mouse model of atherosclerosis. Circulation. 2003; 108: 3017–3023.LinkGoogle Scholar13 Burleigh ME, Babaev VR, Oates JA, Harris RC, Gautam S, Riendeau D, Marnett LJ, Morrow JD, Fazio S, Linton MF. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation. 2002; 105: 1816–1823.LinkGoogle Scholar14 Egan KM, Wang M, Fries S, Lucitt MB, Zukas AM, Pure E, Lawson JA, FitzGerald GA. Cyclooxygenases, thromboxane, and atherosclerosis: plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism. Circulation. 2005; 111: 334–342.LinkGoogle Scholar15 Holmes DR, Wester W, Thompson RW, Reilly JM. Prostaglandin E2 synthesis and cyclooxygenase expression in abdominal aortic aneurysms. J Vasc Surg. 1997; 25: 810–815.CrossrefMedlineGoogle Scholar16 Walton LJ, Franklin IJ, Bayston T, Brown LC, Greenhalgh RM, Taylor GW, Powell JT. Inhibition of prostaglandin E2 synthesis in abdominal aortic aneurysms: implications for smooth muscle cell viability, inflammatory processes, and the expansion of abdominal aortic aneurysms. Circulation. 1999; 100: 48–54.LinkGoogle Scholar17 Miralles M, Wester W, Sicard GA, Thompson R, Reilly JM Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase. J Vasc Surg. 1999 29: 884–892.CrossrefMedlineGoogle Scholar18 Eldor A, Falcone DJ, Hajjar DP, Minick CR, Weksler BB. Recovery of prostacyclin production by de-endothelialized rabbit aorta. Critical role of neointimal smooth muscle cells. J Clin Invest. 1981; 67: 735–741.CrossrefMedlineGoogle Scholar19 Mezzetti A. Pharmacological modulation of plaque instability. Lupus. 2005; 14: 769–772.CrossrefMedlineGoogle Scholar20 Altman R, Luciardi HL, Muntaner J, Del Rio F, Berman SG, Lopez R, Gonzalez C. Efficacy assessment of meloxicam, a preferential cyclooxygenase-2 inhibitor, in acute coronary syndromes without ST-segment elevation: the Nonsteroidal Anti-Inflammatory Drugs in Unstable Angina Treatment-2 (NUT-2) pilot study. Circulation. 2002; 106: 191–195.LinkGoogle Scholar21 King VL, Trivedi D, Gitlin JM, Loftin CD. Selective cyclo-oxygenase-2 inhibition with celecoxib decreases angiotensin II-induced abdominal aortic aneurysm formation in mice. Arterioscler Thromb Vasc Biol. 2006; 26: 1137–1143.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Li B, Wang L, Bai W, Chen W, Chen F and Shu C (2021) Anthocyanins in Health Protection Anthocyanins, 10.1007/978-981-16-7055-8_14, (279-307), . Halim P, Georgey H, George M, El Kerdawy A and Said M (2021) Design and synthesis of novel 4-fluorobenzamide-based derivatives as promising anti-inflammatory and analgesic agents with an enhanced gastric tolerability and COX-inhibitory activity, Bioorganic Chemistry, 10.1016/j.bioorg.2021.105253, 115, (105253), Online publication date: 1-Oct-2021. Nejim B, Weaver M, Locham S, Al-Nouri O, Naazie I and Malas M (2020) Intravenous ketorolac is associated with reduced mortality and morbidity after open abdominal aortic aneurysm repair, Vascular, 10.1177/1708538120914454, 29:1, (15-26), Online publication date: 1-Feb-2021. Said M, Georgey H and Mohammed E (2021) Synthesis and computational studies of novel fused pyrimidinones as a promising scaffold with analgesic, anti-inflammatory and COX inhibitory potential, European Journal of Medicinal Chemistry, 10.1016/j.ejmech.2021.113682, 224, (113682), Online publication date: 1-Nov-2021. Aradhyula V, Waigi E, Bearss N, Edwards J, Joe B, McCarthy C, Koch L and Wenceslau C (2021) Intrinsic exercise capacity induces divergent vascular plasticity via arachidonic acid-mediated inflammatory pathways in female rats, Vascular Pharmacology, 10.1016/j.vph.2021.106862, 140, (106862), Online publication date: 1-Oct-2021. El-Dash Y, Khalil N, Ahmed E and Hassan M (2021) Synthesis and biological evaluation of new nicotinate derivatives as potential anti-inflammatory agents targeting COX-2 enzyme, Bioorganic Chemistry, 10.1016/j.bioorg.2020.104610, 107, (104610), Online publication date: 1-Feb-2021. Hendawy O, Gomaa H, Alzarea S, Alshammari M, Mohamed F, Mostafa Y, Abdelazeem A, Abdelrahman M, Trembleau L and Youssif B (2021) Novel 1,5-diaryl pyrazole-3-carboxamides as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxicity effects, Bioorganic Chemistry, 10.1016/j.bioorg.2021.105302, 116, (105302), Online publication date: 1-Nov-2021. Wollborn J, Steiger C, Ruetten E, Benk C, Kari F, Wunder C, Meinel L, Buerkle H, Schick M and Goebel U (2019) Carbon monoxide improves haemodynamics during extracorporeal resuscitation in pigs, Cardiovascular Research, 10.1093/cvr/cvz075, 116:1, (158-170), Online publication date: 1-Jan-2020. Ahmed E, Kassab A, El-Malah A and Hassan M (2019) Synthesis and biological evaluation of pyridazinone derivatives as selective COX-2 inhibitors and potential anti-inflammatory agents, European Journal of Medicinal Chemistry, 10.1016/j.ejmech.2019.03.036, 171, (25-37), Online publication date: 1-Jun-2019. Brinchmann B, Le Ferrec E, Podechard N, Lagadic-Gossmann D, Holme J and Øvrevik J (2019) Organic chemicals from diesel exhaust particles affects intracellular calcium, inflammation and β-adrenoceptors in endothelial cells, Toxicology Letters, 10.1016/j.toxlet.2018.11.009, 302, (18-27), Online publication date: 1-Mar-2019. Brinchmann B, Skuland T, Rambøl M, Szoke K, Brinchmann J, Gutleb A, Moschini E, Kubátová A, Kukowski K, Le Ferrec E, Lagadic-Gossmann D, Schwarze P, Låg M, Refsnes M, Øvrevik J and Holme J (2018) Lipophilic components of diesel exhaust particles induce pro-inflammatory responses in human endothelial cells through AhR dependent pathway(s), Particle and Fibre Toxicology, 10.1186/s12989-018-0257-1, 15:1, Online publication date: 1-Dec-2018. Moncada S (2018) The Vascular Endothelium Endothelium and Cardiovascular Diseases, 10.1016/B978-0-12-812348-5.00001-5, (5-10), . Tekin G, İsbir S, Şener G, Çevik Ö, Çetinel Ş, Dericioğlu O, Arsan S and Çobanoğlu A (2018) The preventive and curative effects of melatonin against abdominal aortic aneurysm in rats, Journal of Vascular Surgery, 10.1016/j.jvs.2017.04.028, 67:5, (1546-1555), Online publication date: 1-May-2018. Shelmadine B, Bowden R, Moreillon J, Cooke M, Yang P, Deike E, Griggs J and Wilson R (2017) A Pilot Study to Examine the Effects of an Anti-inflammatory Supplement on Eicosanoid Derivatives in Patients with Chronic Kidney Disease, The Journal of Alternative and Complementary Medicine, 10.1089/acm.2016.0007, 23:8, (632-638), Online publication date: 1-Aug-2017. Hassanein H, Georgey H, Fouad M, El Kerdawy A and Said M (2017) Synthesis and molecular docking of new imidazoquinazolinones as analgesic agents and selective COX-2 inhibitors, Future Medicinal Chemistry, 10.4155/fmc-2016-0240, 9:6, (553-578), Online publication date: 1-Apr-2017. Liang Y, Zhen X, Wang K and Ma J (2017) Folic acid attenuates cobalt chloride-induced PGE 2 production in HUVECs via the NO/HIF-1alpha/COX-2 pathway, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2017.06.079, 490:2, (567-573), Online publication date: 1-Aug-2017. Lind M, Hayes A, Caprnda M, Petrovic D, Rodrigo L, Kruzliak P and Zulli A (2017) Inducible nitric oxide synthase: Good or bad?, Biomedicine & Pharmacotherapy, 10.1016/j.biopha.2017.06.036, 93, (370-375), Online publication date: 1-Sep-2017. Deeb R and Hajjar D (2016) Repair Mechanisms in Oxidant-Driven Chronic Inflammatory Disease, The American Journal of Pathology, 10.1016/j.ajpath.2016.03.001, 186:7, (1736-1749), Online publication date: 1-Jul-2016. Chen Y, Shibu M, Fan M, Chen M, Viswanadha V, Lin Y, Lai C, Lin K, Ho T, Kuo W and Huang C (2016) Purple rice anthocyanin extract protects cardiac function in STZ-induced diabetes rat hearts by inhibiting cardiac hypertrophy and fibrosis, The Journal of Nutritional Biochemistry, 10.1016/j.jnutbio.2015.12.020, 31, (98-105), Online publication date: 1-May-2016. Chirisa E and Mukanganyama S (2016) Evaluation of in Vitro Anti-inflammatory and Antioxidant Activity of Selected Zimbabwean Plant Extracts , Journal of Herbs, Spices & Medicinal Plants, 10.1080/10496475.2015.1134745, 22:2, (157-172), Online publication date: 2-Apr-2016. Rullah K, Mohd Aluwi M, Yamin B, Baharuddin M, Ismail N, Teruna H, Bukhari S, Jantan I, Jalil J, Husain K and Wai L (2015) Molecular characterization, biological activity, and in silico study of 2-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-6-methoxy-4H-chromen-4-one as a novel selective COX-2 inhibitor, Journal of Molecular Structure, 10.1016/j.molstruc.2014.10.004, 1081, (51-61), Online publication date: 1-Feb-2015. Watanabe Y, Miyagawa S, Fukushima S, Daimon T, Shirakawa Y, Kuratani T and Sawa Y (2014) Development of a prostacyclin-agonist–eluting aortic stent graft enhancing biological attachment to the aortic wall, The Journal of Thoracic and Cardiovascular Surgery, 10.1016/j.jtcvs.2014.04.024, 148:5, (2325-2334.e1), Online publication date: 1-Nov-2014. Park H, Yang H, Kim G, Son G and Park Y (2014) Microarray analysis of gene expression in 3-methylcholanthrene-treated human endothelial cells, Molecular & Cellular Toxicology, 10.1007/s13273-014-0003-1, 10:1, (19-27), Online publication date: 1-Mar-2014. Elsheikh W, Blackler R, Flannigan K and Wallace J (2014) Enhanced chemopreventive effects of a hydrogen sulfide-releasing anti-inflammatory drug (ATB-346) in experimental colorectal cancer, Nitric Oxide, 10.1016/j.niox.2014.04.006, 41, (131-137), Online publication date: 1-Sep-2014. Askari A, Thomson S, Edin M, Zeldin D and Bishop-Bailey D (2013) Roles of the epoxygenase CYP2J2 in the endothelium, Prostaglandins & Other Lipid Mediators, 10.1016/j.prostaglandins.2013.02.003, 107, (56-63), Online publication date: 1-Dec-2013. Gomez I, Benyahia C, Le Dall J, Payré C, Louedec L, Leséche G, Lambeau G, Longrois D and Norel X (2012) Absence of inflammatory conditions in human varicose saphenous veins, Inflammation Research, 10.1007/s00011-012-0578-8, 62:3, (299-308), Online publication date: 1-Mar-2013. Camacho M, Dilmé J, Solà-Villà D, Rodríguez C, Bellmunt S, Siguero L, Alcolea S, Romero J, Escudero J, Martínez-González J and Vila L (2013) Microvascular COX-2/mPGES-1/EP-4 axis in human abdominal aortic aneurysm, Journal of Lipid Research, 10.1194/jlr.M042481, 54:12, (3506-3515), Online publication date: 1-Dec-2013. Gomez I, Foudi N, Longrois D and Norel X (2013) The role of prostaglandin E2 in human vascular inflammation, Prostaglandins, Leukotrienes and Essential Fatty Acids, 10.1016/j.plefa.2013.04.004, 89:2-3, (55-63), Online publication date: 1-Aug-2013. Yang H, Lee S, Ryu D, Park C, Jin Y and Park Y (2011) Expression profile analysis of human umbilical vein endothelial cells treated with salvianolic acid B from Salvia miltiorrhiza, BioChip Journal, 10.1007/s13206-011-5108-1, 5:1, (47-55), Online publication date: 1-Jan-2011. Jolicoeur E and Granger C (2011) Inflammation and Immunity as Targets for Drug Therapy in Acute Coronary Syndrome Acute Coronary Syndromes: A Companion to Braunwald's Heart Disease, 10.1016/B978-1-4160-4927-2.00025-6, (271-288), . Vila L, Martinez-Perez A, Camacho M, Buil A, Alcolea S, Pujol-Moix N, Soler M, Antón R, Souto J, Fontcuberta J and Soria J (2009) Heritability of Thromboxane A2 and Prostaglandin E2 Biosynthetic Machinery in a Spanish Population, Arteriosclerosis, Thrombosis, and Vascular Biology, 30:1, (128-134), Online publication date: 1-Jan-2010. Liu T, Schneider R, Shah V, Huang Y, Likhotvorik R, Keshvara L and Hoyt D (2009) Protein Never in Mitosis Gene A Interacting-1 regulates calpain activity and the degradation of cyclooxygenase-2 in endothelial cells, Journal of Inflammation, 10.1186/1476-9255-6-20, 6:1, Online publication date: 1-Dec-2009. Saleem S, Shah Z, Urade Y and Doré S (2009) Lipocalin-prostaglandin D synthase is a critical beneficial factor in transient and permanent focal cerebral ischemia, Neuroscience, 10.1016/j.neuroscience.2009.02.039, 160:1, (248-254), Online publication date: 1-Apr-2009. Deeb R, Upmacis R, Lamon B, Gross S and Hajjar D (2007) Maintaining Equilibrium by Selective Targeting of Cyclooxygenase Pathways, Hypertension, 51:1, (1-7), Online publication date: 1-Jan-2008. Shen H, Oesterling E, Stromberg A, Toborek M, MacDonald R and Hennig B (2008) Zinc Deficiency Induces Vascular Pro-Inflammatory Parameters Associated with NF-κB and PPAR Signaling, Journal of the American College of Nutrition, 10.1080/07315724.2008.10719741, 27:5, (577-587), Online publication date: 1-Oct-2008. Camacho M, Rodríguez C, Salazar J, Martínez-González J, Ribalta J, Escudero J, Masana L and Vila L (2008) Retinoic acid induces PGI synthase expression in human endothelial cells, Journal of Lipid Research, 10.1194/jlr.M700559-JLR200, 49:8, (1707-1714), Online publication date: 1-Aug-2008. Wang L, Lim E, Toborek M and Hennig B (2008) The role of fatty acids and caveolin-1 in tumor necrosis factor α–induced endothelial cell activation, Metabolism, 10.1016/j.metabol.2008.01.036, 57:10, (1328-1339), Online publication date: 1-Oct-2008. Griffoni C, Spisni E, Strillacci A, Toni M, Bachschmid M and Tomasi V (2007) Selective inhibition of prostacyclin synthase activity by rofecoxib, Journal of Cellular and Molecular Medicine, 10.1111/j.1582-4934.2007.00021.x, 11:2, (327-338), Online publication date: 1-Mar-2007. Edin M, Lih F, Hammock B, Thomson S, Zeldin D and Bishop-Bailey D (2020) Vascular Lipidomic Profiling of Potential Endogenous Fatty Acid PPAR Ligands Reveals the Coronary Artery as Major Producer of CYP450-Derived Epoxy Fatty Acids, Cells, 10.3390/cells9051096, 9:5, (1096) Sanphetchaloemchok P, Aluwi M, Rullah K and Lam K (2020) Synthesis, In Silico Molecular Docking Modeling and Pharmacophore Mapping of (E)-3-(4-Hydroxy-2,6-Dimethoxyphenyl)-1-Phenylprop-2-en-1-One as Potential New Inhibitor of Microsomal Prostaglandin E2 Synthase-1, Materials Science Forum, 10.4028/www.scientific.net/MSF.981.247, 981, (247-252) Hassan M, Ahmed E, El‐Malah A and Kassab A (2022) Anti‐inflammatory activity of pyridazinones: A review, Archiv der Pharmazie, 10.1002/ardp.202200067 Solà-Villà D, Dilmé J, Rodríguez C, Soto B, Vila L, Escudero J, Martínez-González J, Camacho M and Bader M (2015) Expression and Cellular Localization of 15-Hydroxy-Prostaglandin-Dehydrogenase in Abdominal Aortic Aneurysm, PLOS ONE, 10.1371/journal.pone.0136201, 10:8, (e0136201) May 2006Vol 26, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/01.ATV.0000219672.68024.bcPMID: 16627818 Originally publishedMay 1, 2006 PDF download Advertisement