siiclogo2c.gif (4671 bytes)
CICLOOXIGENASA 2: ¿UNA NUEVA DIANA TERAPEUTICA EN LA ATEROSCLEROSIS
(especial para SIIC © Derechos reservados)
bbbb
cccc

un.jpg paramo9.jpg Autor:
José A. Páramo
Columnista Experto de SIIC

Institución:
 Laboratorio de Aterosclerosis, Centro para la Investigación Médica Aplicada (CIMA)

Artículos publicados por José A. Páramo 

Recepción del artículo: 24 de noviembre, 2005

Aprobación: 3 de enero, 2006

Primera edición: 7 de junio, 2021
Segunda edición, ampliada y corregida:  7 de junio, 2021

Conclusión breve
La ciclooxigenasa 2 (COX-2), una enzima clave en la generación de prostaglandinas proinflamatorias, como PGE2, parece jugar un papel importante en diversas fases de la aterosclerosis. Resultados recientes de nuestro grupo indican que puede, asimismo, constituir un marcador no invasivo de riesgo aterosclerótico, al haberse detectado incremento de PGE2 en relación con los marcadores tradicionales de riesgo aterosclerótico y con el espesor íntima-media de la carótida, un marcador no invasivo de aterosclerosis subclínica. La posibilidad de modular la actividad de COX-2, o de prostaglandinas derivadas de su efecto, puede representar una nueva alternativa en la prevención y tratamiento de la aterosclerosis. Sin embargo, existe controversia sobre el empleo de inhibidores electivos de COX-2 por su posible riesgo cardiovascular.

Resumen

En la actualidad se acepta que la aterosclerosis es un proceso inflamatorio crónico de la pared arterial asociado con la presencia de diversos factores de riesgo. Desde las fases iniciales hasta la ruptura de una placa aterosclerótica vulnerable, un estado de “microinflamación vascular” juega un papel fisiopatológico relevante. Diversos marcadores inflamatorios (CRP, citocinas, moléculas de adhesión), demostraron un papel importante en este proceso inflamatorio. Evidencias clínicas y experimentales también indican que la ciclooxigenasa 2 (COX-2), una enzima que cataliza la generación de prostaglandinas a partir del ácido araquidónico, también contribuye al desarrollo de la lesión aterosclerótica. Nuestro grupo demostró recientemente asociación de PGE2, un metabolito derivado de COX-2 en monocitos, con factores de riesgo y espesor íntima-media de la carótida en un grupo de sujetos asintomáticos, lo que sugiere que la vía COX-2/PGE2 podría jugar un papel en la aterosclerosis y representar una nueva diana terapéutica. Desde el punto de vista teórico, los inhibidores selectivos de la COX-2, denominados genéricamente coxibs (celecoxib, rofecoxib, valdecoxib, lumiracoxib, etc.), podrían ser útiles como fármacos antiinflamatorios en este proceso, sin los efectos secundarios de la aspirina u otros antiinflamatorios no esteroides. Sin embargo, diversos estudios clínicos sugieren que pueden inducir una aumento de complicaciones cardiovasculares, por alteración del equilibrio tromboxano/prostaciclina, por lo que su uso debe restringirse, especialmente en pacientes con alto riesgo aterosclerótico.

Palabras clave
Ciclooxigenasa 2, aterotrombosis, prostaglandina E2, inflamación, coxibs, riesgo cardiovascular

Clasificación en siicsalud
Artículos originales> Expertos del Mundo>
página www.siicsalud.com/des/expertos.php/78027

Especialidades
Principal: Cardiología, 
Relacionadas: Bioquímica, Diagnóstico por Laboratorio, Farmacología, Medicina Farmacéutica, Medicina Interna, 

Enviar correspondencia a:
José. A. Páramo. Laboratorio de Aterosclerosis. CIMA. 31008-Pamplona, Navarra, España

CYCLOOXYGENASE-2: A NEW THERAPEUTIC TARGET IN ATHEROSCLEROSIS

Abstract
It is now widely accepted that atherosclerosis is a complex chronic inflammatory disorder of the arterial tree associated with several risk factors. From the initial phases to eventual rupture of vulnerable atherosclerotic plaques, a low-grade inflammation, also called microinflammation, appears to play a key pathogenetic role. Systemic inflammatory markers (CRP, cytokines adhesion moleculaes) also play a role in this process. Experimental and clinical evidence suggests that cyclooxygenase-2 (COX-2), an enzyme which catalyzes the generation of prostaglandins from arachidonic acid, also contributes to lesion formation. Recent reports by our group have demonstrated increased monocyte COX-2 activity and the production of PGE2 in relation to cardiovascular risk factors and subclinical atherosclerosis in asymptomatic subjects. Our findings support the notion that the COX-2/PGE2 axis may have a role, raising the question as to whether its selective inhibition might be an attractive therapeutic target in atherosclerosis. COX-2 inhibitors, collectively called coxibs (celecoxib, rofecoxib, valdecoxib, lumiracoxib, etc.), might be a promise as anti-inflammatory drugs without some of the side effects of aspirin or non steroidal antiinflammatory agents. However, clinical studies raise several clinically relevant questions in reference to their beneficial role in atherosclerosis prevention. Because of increased thrombogenicity and cardiovascular risk, coxibs should be restricted in atherosclerosis-prone patients.

Key words
Cyclooxygenase-2, atherothrombosis, prostaglandin E2, inflammation, coxibs, cardiovascular risk

CICLOOXIGENASA 2: ¿UNA NUEVA DIANA TERAPEUTICA EN LA ATEROSCLEROSIS

(especial para SIIC © Derechos reservados)

Artículo completo



Bibliografía del artículo

  1. Lusis AJ. Atherosclerosis. Nature 2000; 407:233-241.
  2. Libby P. Inflammation in atherosclerosis. Nature 2002; 420:868-874.
  3. Libby P, Ridker PM, Masseri A. Inflammation and atherosclerosis. Circulation 2002; 105:1135-1143.
  4. Naghavi M, Libby P, Falk E, y col. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Parts I and II. Circulation 2003; 108:1664-1672 and 1772-1778.
  5. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001; 103:1813-1818.
  6. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347:1557-1565.
  7. Dubois RN, Abramson SB, Crofford L, y col. Cyclooxygenase in biology and disease. FASEB J. 1998; 12:1063-1073.
  8. Patrono C. Aspirin: new cardiovascular uses for an old drug. Am J Med. 2001; 110:62S-65S.
  9. Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem. 1996; 271:33157-33160.
  10. Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem. 2000; 69:145-182.
  11. Yokoyama C, Tanabe T. Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme. Biochim Biophys Res Commun 1989; 165:888-894.
  12. Kosaka T, Miyata A, Ihara H, y col. Characterization of the human gene (PTGS2) encoding prostaglandin endoperoxide synthase 2. Eur J Biochem 1994; 221:889-897.
  13. Dixon DA, Kaplan CD, McIntyre TM, Zimmerman GA, Prescott SM. Post-transcriptional control of cyclooxygenase-2 gene expression: the role of the 3'-untranslated region. J Biol Chem 2000; 275:11750-11757.
  14. Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med. 1999; 5:698-701.
  15. Vila L. Cyclooxygenase and 5-lypooxygenase pathways in the vessel wall: role in atherosclerosis. Medicinal Research Rev 2004; 24:399-424.
  16. Chandrasekharan NV, Dai H, Roos KL, y col. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci, USA 2002; 99:13926-13931.
  17. Egan KM, Lawson JA, Fries S, y col. COX-2 derived prostacyclin confers atheroprotection on female mice. Science 2004; 306:1954-1957.
  18. Wu KK, Lion JY, Cierlik K. Transcriptional control of COX-2 via c/EBP-ß Arterioscler Thromb Vasc Biol 2005; 25:679-685.
  19. McAdam BF, Mardini IA, Habib A, y col. Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation. J Clin Invest. 2000; 105:1473-82.
  20. Tilley SL, Coffman TM, Koller BH. Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes. J Clin Invest. 2001; 108:15-23.
  21. 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 USA. 1999; 96:272-277.
  22. Belton O, Byrne D, Kearney D, Leahy A, Fitzgerald DJ. Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation. 2000; 102:840-845.
  23. Cipollone F, Rocca B, Patrono C. Cyclooxygenase-2 expression and inhibition in atherothrombosis. Arterioscler Thromb Vasc Biol 2004; 24:246-255.
  24. Natarajan R, Naddler JL. Lipid inflammatory mediators in diabetic vascular disease. Arterioscler Thromb Vasc Biol 2004; 24:1542-1548.
  25. Belt AR, Baldassare JJ, Molnar M, Romero R, Hertelendy F. The nuclear transcription factor NF-kappaB mediates interleukin-1beta-induced expression of cyclooxygenase-2 in human myometrial cells. Am J Obstet Gynecol. 1999; 181:359-366
  26. Jambou D, Dejour N, Bayer P, y col. Effect of human native low-density and high-density lipoproteins on prostaglandin production by mouse macrophage cell line P388D1: possible implications in pathogenesis of atherosclerosis. Biochim Biophys Acta. 1993; 1168:115-121.
  27. Adderley SR, Fitzgerald DJ. Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2. J Biol Chem. 1999; 274:5038-5046.
  28. Murphy JF, Fitzgerald DJ. Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. FASEB J. 2001; 15:1667-1669.
  29. Davidge ST. Prostaglandin H synthase and vascular function. Circ Res 2001; 89:650-660.
  30. Pritchard KA Jr, O'Nanion MK, Miano JM, y col. Induction of cyclooxygenase-2 in rat vascular smooth muscle cells in vitro and in vivo. J Biol Chem 1994; 269:8504-8509.
  31. Baker CS, Hall RJ, Evans TJ, y col. 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.
  32. Schönbeck U, Sukhova GK, Graber P, Coulter S, Libby P. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol. 1999; 155:1281-1291.
  33. Linton MF, Fazio S. Cyclooxygenase-2 and inflammation in atherosclerosis. Curr Opin Pharmacol 2004; 4:116-123.
  34. Corcoran ML, Stetler-Stevenson WG, DeWitt DL, Wahl LM. Effect of cholera toxin and pertussis toxin on prostaglandin H synthase-2, prostaglandin E2, and matrix metalloproteinase production by human monocytes. Arch Biochem Biophys. 1994; 310:481-418.
  35. Cipollone F, Prontera C, Pini B, y col. Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E(2)-dependent plaque instability. Circulation. 2001; 104:921-927.
  36. Cipollone F, Fazia M, Iezzi A, y col. The functionally coupled cyclooxygenasese-2/Prostaglandin E2 as a basis of simvastatin-dependent plaque stabilization in humans. Circulation 2003; 107:1479-1485.
  37. Cipollone F, Fazia M, Iezzi A, y col. Balance between PGD synthase and PGE-synthase is a major determinant of atherosclerotic plaque instability in humans. Arterioscler Thromb Vasc Biol 2004; 24:1259-1265.
  38. Serhan CN, Levy B. Success of prostaglandin E2 in structure-function is a challenge for structure-based therapeutics. Proc Nat Acad Sci, USA 2003; 100:8609-8611.
  39. Inohue H, Tanabe T, Umesono K. Feedback control of cyclooxygenase-2 expression through PPAR gamma. J Biol Chem 2000; 275:28028-28032.
  40. Fitzgerald DA, Austin S, Egan K, Cheng Y, Pratico D. Cyclo-oxygenase products and atherothrombosis. Ann Med 2000; 32 (Suppl 1):21-26.
  41. Kobayashi T, Tahara Y, Matsumoto M, y col. Roles of thromboxane A (2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice. J Clin Invest 2004; 114:784-794.
  42. Murata T, Ushikubi F, Matsuoka T, y col. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 1997; 388:678-682.
  43. Egan KM, Wang M, Lucitt MB, y col. Cyclooxygenases, thromboxane, and atherosclerosis. Plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism. Circulation 2005; 111:334-342.
  44. Beloqui O, Páramo JA, Orbe J, y col. Monocyte cyclooxygenase-2 overactivity: a new marker of subclinical atherosclerosis in asymptomatic subjects with cardiovascular risk factors. Eur Heart J 2005; 26:153-158.
  45. Patrignani P, Panara MR, Greco A, y col. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthase. J Pharmacol Exp Ther 1994; 271:1705-1712.
  46. Turini ME, DuBois RN. Cyclooxygenase-2: a therapeutic target. Annu Rev Med 2002; 53:35-57.
  47. Páramo JA, Rodríguez JA, Beloqui O, Orbe J. Monocyte cyclooxygenase-2 activity: a new therapeutic target for atherosclerosis Current Drug Targets-Cardiovascular&Haematological disorders 2005; 5:303-311.
  48. De Gaetano G, Donatti MB, Cerletti C. Prevention of thrombosis and vascular inflammation: benefits and limitations of selective or combined COX-1, COX-2 and 5-LOX inhibitors. Trends Pharmacol Sci 2003; 24:245-252.
  49. Van Hecken A, Schwartz JI, Depre M, y col. Comparative inhibitor activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol 2000; 40:1109-1120.
  50. Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345:433-442.
  51. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest. 2004; 126 (Suppl 3):234S-264S.
  52. Burleigh ME, Babaev VR, Oates JA, y col. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL-receptor deficient mice. Circulation 2002; 105:1816-1823.
  53. Yang HM, Kim H-S, Park K-W, y col. Celecoxib, a cyclooxygenase-2 inhibitor, reduces neointimal hyperplasia through inhibition of Akt signaling. Circulation 2004; 110:301-308.
  54. Pratico D, Tillmann C, Zhang ZB, Li H, FitzGerald GA. Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice. Proc Natl Acad Sci U S A. 2001; 98:3358-3363.
  55. Olesen M, Kwong E, Meztli A, y col. No effect of cyclooxygenase inhibition on plaque size in atherosclerosis-prone mice. Scand Cardiovasc J 2002; 36:362-367.
  56. Rott D, Zhu J, Burnett MS, Zhou YF, y col. Effect of MF-tricyclic, a selective cyclooxygenase-2 inhibitor, on atherosclerosis progression and susceptibility to cytomegalovirus replication in apolipoprotein-E knockout mice. J Am Coll Cardiol 2003; 41:1812-1816.
  57. Dowd NP, Scully M, Adderley SR, Cunningham AJ, Fitzgerlad DJ. Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo. J Clin Invest 2001; 108:585-590.
  58. Delgado RM 3rd, Nawor MA, Zewail AM, y col. Cyclooxygenase-2 inhibitor treatment improved left ventricular function and mortality in a murine model of doxorubicin-induced heart failure. Circulation 2004; 109:1428-1433.
  59. Widlansky ME, Price DT, Gokce N, y col. Short- and long-term COX-2 inhibition reverses endothelial dysfunction in patients with hypertension. Hypertension 2003; 42:310-315.
  60. Chenevard R, Hürlimann D, Béchir M, y col. Selective COX-2 inhibition improves endothelial function in coronary artery disease. Circulation 2003; 107:405-409.
  61. Bogaty P, Brophy JM, Noel M, y col. Impact of prolonged cyclooxygenase-2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein: a randomized placebo-controlled study. Circulation 2004; 110:934-939.
  62. Catella-Lawson F, Crofford LJ. Cyclooxygenase inhibition and thrombogenicity. Am J Med. 2001; 110 Suppl 3A:28S-32S.
  63. Pitt B, Peppine C, Wilerson JT. Cyclooxygenase inhibition and cardiovascular events. Circulation 2002; 106:167-169.
  64. Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk. Circulation 2005; 112:759-770.
  65. Bombardier C, Laine L, Reicin A, y col. 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.
  66. Bresalier RS, Sandler RS, Quan H,Bolognesey col, for the Adenomatous Polyp Prevention on Viox (APPROVe) trial investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352:1092-1102.
  67. Silverstein FE, Faich G, Goldstein JL, y col. 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. 2000; 284:1247-1255.
  68. White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 2003; 92:411-418.
  69. Farkouh ME, Kirshner H, Ruland S, y col. Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research gastrointestinal event trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004; 364:675-684.
  70. Solomon SD, McMurray JJ, Pfeffer MA, y col, for the Adenoma Prevention with Celecoxib (APC) study investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352:1071-1080.
  71. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001; 286:954-9.
  72. Juni P, Nartery L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events with rofecoxib: cumulative meta-analysis. Lancet 2004; 364:2021-2029.
  73. Chang IJ, Harris RC. Are all COX-2 inhibitors created equal . Hypertension 2005; 45:178-180.
  74. Fitzgerald GA. COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat Rev 2003; 2:879-890.
  75. Topol EJ, Falk GW. Coxib a day won’t keep the doctor away. Lancet 2004; 364:639-640.
  76. Couzin J. Clinical trilas. Nail-biting time for trials of COX-2 drugs. Science 2004; 306:1673-1675.
  77. Vanchieri C. Viox withdrawall alarmas cancer prevention researchers. J Natl Cancer Inst 2004; 96:1734-1735.
  78. Rotondo S, Dell’Elba G, Krauze-Brzosko K, y col. Licofelone, a dual lipooxygenase-cyclooxygenase inhibitor, downregulates polymorphonuclear leukocytes and platelet function. Eur J Pharmacol 2002; 453:131-139.
© Está  expresamente prohibida la redistribución y la redifusión de todo o parte de los  contenidos de la Sociedad Iberoamericana de Información Científica (SIIC) S.A. sin  previo y expreso consentimiento de SIIC

anterior.gif (1015 bytes)

 

Bienvenidos a siicsalud
Acerca de SIIC Estructura de SIIC

Sociedad Iberoamericana de Información Científica (SIIC)
Arias 2624, (C1429DXT), Buenos Aires, Argentina atencionallector@siicsalud.com;  Tel: +54 11 4702-1011 / 4702-3911 / 4702-3917
Casilla de Correo 2568, (C1000WAZ) Correo Central, Buenos Aires.
Copyright siicsalud© 1997-2024, Sociedad Iberoamericana de Información Científica(SIIC)