(Circulation. 1999;100:614-620.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Enhanced Levels of Soluble and Membrane-Bound CD40 Ligand in Patients With Unstable Angina
Possible Reflection of T Lymphocyte and Platelet Involvement in the Pathogenesis of Acute Coronary Syndromes
From the Section of Clinical Immunology and Infectious Diseases (P.A., F.M., S.S.F.), Research Institute for Internal Medicine (P.A., F.M., N.O.S., S.S.F.), Section of Endocrinology, Medical Department (T.U.), and Department of Cardiology, Division of Heart and Lung Diseases (T.B., E.A., A.B., K.F., L.G.), University of Oslo, Rikshospitalet, Oslo, Norway.
Background—The CD40 ligand (CD40L) on activated T cells and platelets may be activating matrix metalloproteinases, inducing procoagulant activity, and be involved in the pathogenesis of acute coronary syndromes by promoting plaque rupture in atheroma.
Methods and Results—To study the role of CD40L-CD40 interaction in coronary disease, we analyzed levels of soluble (s) and membrane-bound CD40L in the peripheral blood from 29 patients with stable angina, 26 with unstable angina, and 19 controls. Our main findings follow. (1) Patients with unstable angina had significantly raised serum levels of sCD40L when compared with patients with stable angina and controls. (2) Platelets could release large amounts of sCD40L when stimulated ex vivo with the thrombin receptor–agonist peptide SFLLRN in both patients and controls. (3) Platelets in patients with unstable angina were characterized ex vivo by decreased intracellular levels and decreased SFLLRN-stimulated release of sCD40L, which may possibly represent a higher percentage of degranulated platelets in these patients. (4) T cells in patients with unstable angina had enhanced surface expression of CD40L and increased release of sCD40L on anti-CD3/anti-CD28 stimulation in vitro when compared with patients with stable angina and controls. (5) Recombinant CD40L and serum from patients with unstable angina who had high sCD40L levels induced enhanced release of monocyte chemoattractant peptide-1 from mononuclear cells, a CC-chemokine involved in the pathogenesis of atherosclerosis.
Conclusions—This first demonstration of enhanced levels of soluble and membrane-bound forms of CD40L in angina patients, with particularly high levels in patients with unstable angina, suggests that CD40L-CD40 interaction may play a pathogenic role in both the long-term atherosclerotic process and in the triggering and propagation of acute coronary syndromes.
Key Words: angina • platelets • T cells • immunology • CD40 • atherosclerosis
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C. Heeschen, S. Dimmeler, C. W. Hamm, M. J. van den Brand, E. Boersma, A. M. Zeiher, M. L. Simoons, and the CAPTURE Study Investigators Soluble CD40 Ligand in Acute Coronary Syndromes N. Engl. J. Med., March 20, 2003; 348(12): 1104 - 1111. [Abstract] [Full Text] [PDF]
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L. Nannizzi-Alaimo, V. L. Alves, and D. R. Phillips Inhibitory Effects of Glycoprotein IIb/IIIa Antagonists and Aspirin on the Release of Soluble CD40 Ligand During Platelet Stimulation Circulation, March 4, 2003; 107(8): 1123 - 1128. [Abstract] [Full Text] [PDF]
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 C.-L. Wang, Y.-T. Wu, C.-A. Liu, M.-W. Lin, C.-J. Lee, L.-T. Huang, and K. D. Yang Expression of CD40 Ligand on CD4+ T-Cells and Platelets Correlated to the Coronary Artery Lesion and Disease Progress in Kawasaki Disease Pediatrics, February 1, 2003; 111(2): e140 - 147. [Abstract] [Full Text] [PDF]
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A. G. Semb, S. van Wissen, T. Ueland, T. Smilde, T. Waehre, M. D. Tripp, S. S. Froland, J. J. P. Kastelein, L. Gullestad, T. R. Pedersen, et al. Raised serum levels of soluble CD40 ligand in patients with familial hypercholesterolemia: downregulatory effect of statin therapy J. Am. Coll. Cardiol., January 15, 2003; 41(2): 275 - 279. [Abstract] [Full Text] [PDF]
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U. Schonbeck, N. Gerdes, N. Varo, R. S. Reynolds, D. B. Horton, U. Bavendiek, L. Robbie, P. Ganz, S. Kinlay, and P. Libby Oxidized Low-Density Lipoprotein Augments and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Limit CD40 and CD40L Expression in Human Vascular Cells Circulation, December 3, 2002; 106(23): 2888 - 2893. [Abstract] [Full Text] [PDF]
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P. Andre, L. Nannizzi-Alaimo, S. K. Prasad, and D. R. Phillips Platelet-Derived CD40L: The Switch-Hitting Player of Cardiovascular Disease Circulation, August 20, 2002; 106(8): 896 - 899. [Full Text] [PDF]
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C. Urbich, E. Dernbach, A. Aicher, A. M. Zeiher, and S. Dimmeler CD40 Ligand Inhibits Endothelial Cell Migration by Increasing Production of Endothelial Reactive Oxygen Species Circulation, August 20, 2002; 106(8): 981 - 986. [Abstract] [Full Text] [PDF]
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F. Cipollone, A. Mezzetti, E. Porreca, C. Di Febbo, M. Nutini, M. Fazia, A. Falco, F. Cuccurullo, and G. Davi Association Between Enhanced Soluble CD40L and Prothrombotic State in Hypercholesterolemia: Effects of Statin Therapy Circulation, July 23, 2002; 106(4): 399 - 402. [Abstract] [Full Text] [PDF]
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L. Nannizzi-Alaimo, M. H. Rubenstein, V. L. Alves, G. Y. Leong, D. R. Phillips, and H. K. Gold Cardiopulmonary Bypass Induces Release of Soluble CD40 Ligand Circulation, June 18, 2002; 105(24): 2849 - 2854. [Abstract] [Full Text] [PDF]
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J.-F. Viallard, A. Solanilla, B. Gauthier, C. Contin, J. Dechanet, C. Grosset, J.-F. Moreau, V. Praloran, P. Nurden, J.-L. Pellegrin, et al. Increased soluble and platelet-associated CD40 ligand in essential thrombocythemia and reactive thrombocytosis Blood, April 1, 2002; 99(7): 2612 - 2614. [Abstract] [Full Text] [PDF]
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 A. Maseri and D. Cianflone Inflammation in acute coronary syndromes Eur. Heart J. Suppl., March 1, 2002; 4(suppl_B): B8 - B13. [Abstract] [PDF]
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U. Schonbeck and P. Libby CD40 Signaling and Plaque Instability Circ. Res., December 7, 2001; 89(12): 1092 - 1103. [Abstract] [Full Text] [PDF]
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P. AUKRUST, T. WAeHRE, J. K. DAMAS, L. GULLESTAD, and N. O. SOLUM Inflammatory role of platelets in acute coronary syndromes Heart, December 1, 2001; 86(6): 605 - 606. [Full Text] [PDF]
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C D Garlichs, S Eskafi, D Raaz, A Schmidt, J Ludwig, M Herrmann, L Klinghammer, W G Daniel, and A Schmeisser Patients with acute coronary syndromes express enhanced CD40 ligand/CD154 on platelets Heart, December 1, 2001; 86(6): 649 - 655. [Abstract] [Full Text] [PDF]
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C. D. Garlichs, S. John, A. Schmei{beta}er, S. Eskafi, C. Stumpf, M. Karl, M. Goppelt-Struebe, R. Schmieder, and W. G. Daniel Upregulation of CD40 and CD40 Ligand (CD154) in Patients With Moderate Hypercholesterolemia Circulation, November 13, 2001; 104(20): 2395 - 2400. [Abstract] [Full Text] [PDF]
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U. Schonbeck, N. Varo, P. Libby, J. Buring, and P. M. Ridker Soluble CD40L and Cardiovascular Risk in Women Circulation, November 6, 2001; 104(19): 2266 - 2268. [Abstract] [Full Text] [PDF]
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P.a. Aukrust, R. K. Berge, T. Ueland, E. Aaser, J. K. Damas, L. Wikeby, A. Brunsvig, F. Muller, K. Forfang, S. S. Froland, et al. Interaction between chemokines and oxidative stress: possible pathogenic role in acute coronary syndromes J. Am. Coll. Cardiol., February 1, 2001; 37(2): 485 - 491. [Abstract] [Full Text] [PDF]
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R. P. Phipps Atherosclerosis: The emerging role of inflammation and the CD40-CD40 ligand system PNAS, June 20, 2000; 97(13): 6930 - 6932. [Full Text] [PDF]
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E. Lutgens, K. B. J. M. Cleutjens, S. Heeneman, V. E. Koteliansky, L. C. Burkly, and M. J. A. P. Daemen Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype PNAS, June 20, 2000; 97(13): 7464 - 7469. [Abstract] [Full Text] [PDF]
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 T. A. Waldmann, R. Levy, and B. S. Coller Emerging Therapies: Spectrum of Applications of Monoclonal Antibody Therapy Hematology, January 1, 2000; 2000(1): 394 - 408. [Abstract] [Full Text] [PDF]
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