Circulation. 2001;104:921-927
doi: 10.1161/hc3401.093152
doi: 10.1161/hc3401.093152
(Circulation. 2001;104:921.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Overexpression of Functionally Coupled Cyclooxygenase-2 and Prostaglandin E Synthase in Symptomatic Atherosclerotic Plaques as a Basis of Prostaglandin E2-Dependent Plaque Instability
From the University of Chieti, G. D’Annunzio School of Medicine, Chieti, and INRCA, University of Ancona School of Medicine (V.S.), Ancona, Italy.
Correspondence to Andrea Mezzetti, MD, Centro per la Prevenzione dell’Aterosclerosi, la Diagnosi e Terapia dell’Ipertensione Arteriosa e delle Dislipidemie, Nuovo Policlinico SS. Annunziata, Via dei Vestini 66, 66013 Chieti, Italy. E-mail mezzetti{at}unich.it
Background—— Studies have implicated a role for prostaglandin (PG) E2-dependent matrix metalloproteinase (MMP) biosynthesis in the rupture of atherosclerotic plaque. Cyclooxygenase-2 (COX-2) and PGE synthase (PGES) are coregulated in nucleated cells by inflammatory stimuli. The aim of this study was to characterize the expression of COX-2 and PGES in carotid plaques and to correlate it with the extent of inflammatory infiltration and MMP activity and with clinical features of patients’ presentation.
Methods and Results—— Plaques were obtained from 50 patients undergoing carotid endarterectomy and divided into 2 groups (symptomatic and asymptomatic) according to clinical evidence of recent transient ischemic attack or stroke. Plaques were analyzed for COX-2, PGES, MMP-2, and MMP-9 by immunocytochemistry and Western blot, whereas zymography was used to detect MMP activity. Immunocytochemistry was used to identify CD68+ macrophages, CD3+ T lymphocytes, and HLA-DR+ cells. The percentage of macrophage-rich areas was larger (P<0.0001) in symptomatic plaques. COX-2, PGES, and MMPs were detected in all specimens; enzyme concentration, however, was significantly higher in symptomatic plaques. COX-2, PGES, and MMPs were especially noted in shoulders of symptomatic plaques, colocalizing with HLA-DR+ macrophages. All symptomatic plaques contained activated forms of MMPs. Finally, inhibition of COX-2 by NS-398 was accompanied by decreased production of MMPs that was reversed by PGE2.
Conclusions—— This study demonstrates the colocalization of COX-2 and PGES in symptomatic lesions and provides evidence that synthesis of COX-2 and PGES by activated macrophages is associated with acute ischemic syndromes, possibly through metalloproteinase-induced plaque rupture.
Key Words: atherosclerosis • plaque • prostaglandins • metalloproteinases • inflammation
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S. Thoren, R. Weinander, S. Saha, C. Jegerschold, P. L. Pettersson, B. Samuelsson, H. Hebert, M. Hamberg, R. Morgenstern, and P.-J. Jakobsson Human Microsomal Prostaglandin E Synthase-1: PURIFICATION, FUNCTIONAL CHARACTERIZATION, AND PROJECTION STRUCTURE DETERMINATION J. Biol. Chem., June 13, 2003; 278(25): 22199 - 22209. [Abstract] [Full Text] [PDF]
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E. Tuleja, F. Mejza, A. Cmiel, and A. Szczeklik Effects of Cyclooxygenases Inhibitors on Vasoactive Prostanoids and Thrombin Generation at the Site of Microvascular Injury in Healthy Men Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1111 - 1115. [Abstract] [Full Text] [PDF]
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D. Rott, J. Zhu, M. S. Burnett, Y. i F. u Zhou, A. Zalles-Ganley, J. Ogunmakinwa, and S. E. Epstein Effects 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., May 21, 2003; 41(10): 1812 - 1819. [Abstract] [Full Text] [PDF]
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O. Belton and D. Fitzgerald Cyclooxygenase-2 inhibitors and atherosclerosis J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1820 - 1822. [Full Text] [PDF]
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F. Cipollone, A. Ganci, A. Greco, M. R. Panara, M. Pasquale, D. Di Gregorio, E. Porreca, A. Mezzetti, F. Cuccurullo, and P. Patrignani Modulation of Aspirin-Insensitive Eicosanoid Biosynthesis by 6-Methylprednisolone in Unstable Angina Circulation, January 7, 2003; 107(1): 55 - 61. [Abstract] [Full Text] [PDF]
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K. Takayama, G. Garcia-Cardena, G. K. Sukhova, J. Comander, M. A. Gimbrone Jr., and P. Libby Prostaglandin E2 Suppresses Chemokine Production in Human Macrophages through the EP4 Receptor J. Biol. Chem., November 8, 2002; 277(46): 44147 - 44154. [Abstract] [Full Text] [PDF]
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F. Cipollone and C. Patrono Cyclooxygenase-2 Polymorphism: Putting a Brake on the Inflammatory Response to Vascular Injury? Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1516 - 1518. [Full Text] [PDF]
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B. Rocca, P. Secchiero, G. Ciabattoni, F. O. Ranelletti, L. Catani, L. Guidotti, E. Melloni, N. Maggiano, G. Zauli, and C. Patrono Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets PNAS, May 28, 2002; 99(11): 7634 - 7639. [Abstract] [Full Text] [PDF]
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M. K. Halushka and P. V. Halushka Why Are Some Individuals Resistant to the Cardioprotective Effects of Aspirin?: Could It Be Thromboxane A2? Circulation, April 9, 2002; 105(14): 1620 - 1622. [Full Text] [PDF]
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A. V. Pontsler, A. St. Hilaire, G. K. Marathe, G. A. Zimmerman, and T. M. McIntyre Cyclooxygenase-2 Is Induced in Monocytes by Peroxisome Proliferator Activated Receptor gamma and Oxidized Alkyl Phospholipids from Oxidized Low Density Lipoprotein J. Biol. Chem., April 5, 2002; 277(15): 13029 - 13036. [Abstract] [Full Text] [PDF]
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E. Connolly, D. J. Bouchier-Hayes, E. Kaye, A. Leahy, D. Fitzgerald, and O. Belton Cyclooxygenase Isozyme Expression and Intimal Hyperplasia in a Rat Model of Balloon Angioplasty J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 393 - 398. [Abstract] [Full Text] [PDF]
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J. W. Eikelboom, J. Hirsh, J. I. Weitz, M. Johnston, Q. Yi, and S. Yusuf Aspirin-Resistant Thromboxane Biosynthesis and the Risk of Myocardial Infarction, Stroke, or Cardiovascular Death in Patients at High Risk for Cardiovascular Events Circulation, April 9, 2002; 105(14): 1650 - 1655. [Abstract] [Full Text] [PDF]
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