Circulation Research. 2001;89:1092-1103
doi: 10.1161/hh2401.101272
doi: 10.1161/hh2401.101272
© 2001 American Heart Association, Inc.
Reviews |
CD40 Signaling and Plaque Instability
From the Leducq Center for Cardiovascular Research, Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Uwe Schönbeck, Leducq Center for Cardiovascular Research, Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 309, Boston, MA 02115. E-mail uschoenbeck{at}rics.bwh.harvard.edu
Abstract
Today, multiple lines of evidence support the view of atherosclerosis as a chronic inflammatory disease and implicate components of the immune system in atherogenesis. Recent work has documented overexpression of the potent immune mediator CD40 and its counterpart CD40 ligand (CD40L) in experimental and human atherosclerotic lesions. Notably, interruption of CD40/CD40L interactions not only diminished the formation and progression of mouse atheroma, but also fostered changes in lesion biology and structure, which are associated in humans with "plaque stabilization." In accordance with the hypothesis that CD40 signaling promotes plaque instability, in vitro studies demonstrated that ligation of CD40 on atheroma-associated cell types, namely endothelial cells, smooth muscle cells, and macrophages, mediates functions considered crucial to the process of atherogenesis, such as the expression of cytokines, chemokines, growth factors, matrix metalloproteinases, and procoagulants. The combination of the broad gamut of proatherogenic biological responses triggered by ligation of CD40 on endothelial cells, smooth muscle cells, and macrophages in vitro and the results of in vivo studies of interruption of CD40 signaling suggests a central role for this receptor/ligand dyad during atherogenesis, proposing CD40/CD40L interactions as a novel potential therapeutic target for this prevalent human disease.
Key Words: CD40 • CD40L • atherosclerosis • inflammation • immunity
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N. Varo, J. A. de Lemos, P. Libby, D. A. Morrow, S. A. Murphy, R. Nuzzo, C. M. Gibson, C. P. Cannon, E. Braunwald, and U. Schonbeck Soluble CD40L: Risk Prediction After Acute Coronary Syndromes Circulation, September 2, 2003; 108(9): 1049 - 1052. [Abstract] [Full Text] [PDF]
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N. Varo, D. Vicent, P. Libby, R. Nuzzo, A. L. Calle-Pascual, M. R. Bernal, A. Fernandez-Cruz, A. Veves, P. Jarolim, J. J. Varo, et al. Elevated Plasma Levels of the Atherogenic Mediator Soluble CD40 Ligand in Diabetic Patients: A Novel Target of Thiazolidinediones Circulation, June 3, 2003; 107(21): 2664 - 2669. [Abstract] [Full Text] [PDF]
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A. J. Grau and C. Lichy Editorial Comment: Stroke and the CD40-CD40 Ligand System: At the Hinge Between Inflammation and Thrombosis Stroke, June 1, 2003; 34(6): 1417 - 1418. [Full Text] [PDF]
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 M. C. Deregibus, S. Buttiglieri, S. Russo, B. Bussolati, and G. Camussi CD40-dependent Activation of Phosphatidylinositol 3-Kinase/Akt Pathway Mediates Endothelial Cell Survival and in Vitro Angiogenesis J. Biol. Chem., May 9, 2003; 278(20): 18008 - 18014. [Abstract] [Full Text] [PDF]
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 J. E. Freedman CD40 Ligand -- Assessing Risk Instead of Damage? N. Engl. J. Med., March 20, 2003; 348(12): 1163 - 1165. [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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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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A. H. Wagner, M. Gebauer, B. Guldenzoph, and M. Hecker 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase-Independent Inhibition of CD40 Expression by Atorvastatin in Human Endothelial Cells Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1784 - 1789. [Abstract] [Full Text] [PDF]
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L. Fuentes, M. Hernandez, F. J. Fernandez-Aviles, M. S. Crespo, and M. L. Nieto Cooperation Between Secretory Phospholipase A2 and TNF-Receptor Superfamily Signaling: Implications for the Inflammatory Response in Atherogenesis Circ. Res., October 18, 2002; 91(8): 681 - 688. [Abstract] [Full Text] [PDF]
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G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [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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