on April 8, 2002
Circulation. 2002
Published online before print April 8, 2002, doi: 10.1161/01.CIR.0000015126.83143.B4
Published online before print April 8, 2002, doi: 10.1161/01.CIR.0000015126.83143.B4
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© American Heart Association, Inc.
Clinical Investigation and Reports |
Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein
From the Division of Cardiac Surgery, Toronto General Hospital Research Institute, University of Toronto, Canada.
Correspondence to Dr Donald A.G. Mickle, Toronto General Hospital, 200 Elizabeth St, Toronto, Canada M5G 2C4, and reprint requests to Dr Subodh Verma (E-mail subodh.verma{at}sympatico.ca).
Background— C-reactive protein (CRP) has been suggested to actively participate in the development of atherosclerosis. In the present study, we examined the role of the potent endothelium-derived vasoactive factor endothelin-1 (ET-1) and the inflammatory cytokine interleukin-6 (IL-6) as mediators of CRP-induced proatherogenic processes.
Methods and Results— Saphenous vein endothelial cells (HSVECs) were incubated with human recombinant CRP (25 µg/mL, 24 hours) and the expression of vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1), and monocyte chemoattractant chemokine-1 was determined. The effects of CRP on LDL uptake were assessed in macrophages using immunofluorescent labeling of CD32 and CD14. In each study, the effect of endothelin antagonism (bosentan) and IL-6 inhibition (monoclonal anti-IL-6 antibodies) was examined. The effects of CRP on the secretion of ET-1 and IL-6 from HSVECs were also evaluated. Incubation of HSVECs with recombinant human CRP resulted in a marked increase in ICAM-1 and VCAM-1 expression (P<0.001). Likewise, CRP caused a significant increase in monocyte chemoattractant chemokine-1 production, a key mediator of leukocyte transmigration (P<0.001). CRP caused a marked and sustained increase in native LDL uptake by macrophages (P<0.05). These proatherosclerotic effects of CRP were mediated, in part, via increased secretion of ET-1 and IL-6 (P<0.01) and were attenuated by both bosentan and IL-6 antagonism (P<0.01).
Conclusions— CRP actively promotes a proatherosclerotic and proinflammatory phenotype. These effects are mediated, in part, via the production of ET-1 and IL-6 and are attenuated by mixed ETA/B receptor antagonism and IL-6 inhibition. Bosentan may be useful in decreasing CRP-mediated vascular disease.
Key Words: protein, C-reactive • cell adhesion molecules • endothelium • atherosclerosis • endothelin
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H.-K. Yip, C.-J. Wu, H.-W. Chang, C.-H. Yang, K.-H. Yeh, S. Chua, and M. Fu Levels and Values of Serum High-Sensitivity C-Reactive Protein Within 6 Hours After the Onset of Acute Myocardial Infarction Chest, November 1, 2004; 126(5): 1417 - 1422. [Abstract] [Full Text] [PDF]
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L. Li, N. Roumeliotis, T. Sawamura, and G. Renier C-Reactive Protein Enhances LOX-1 Expression in Human Aortic Endothelial Cells: Relevance of LOX-1 to C-Reactive Protein-Induced Endothelial Dysfunction Circ. Res., October 29, 2004; 95(9): 877 - 883. [Abstract] [Full Text] [PDF]
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S. Fazel, R. D. Weisel, and S. Verma A novel technique to assess flow-mediated vasodilation J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1478 - 1480. [Full Text] [PDF]
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 D. D. Sin, P. Lacy, E. York, and S. F. P. Man Effects of Fluticasone on Systemic Markers of Inflammation in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 1, 2004; 170(7): 760 - 765. [Abstract] [Full Text] [PDF]
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M. Lambert, E. E. Delvin, G. Paradis, J. O'Loughlin, J. A. Hanley, and E. Levy C-Reactive Protein and Features of the Metabolic Syndrome in a Population-Based Sample of Children and Adolescents Clin. Chem., October 1, 2004; 50(10): 1762 - 1768. [Abstract] [Full Text] [PDF]
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D. Fliser, K. Buchholz, H. Haller, and for the EUropean Trial on Olmesartan and Pravastat Antiinflammatory Effects of Angiotensin II Subtype 1 Receptor Blockade in Hypertensive Patients With Microinflammation Circulation, August 31, 2004; 110(9): 1103 - 1107. [Abstract] [Full Text] [PDF]
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S. P. Zhao, L. Liu, Y. C. Cheng, M. H. Shishehbor, M. H. Liu, D. Q. Peng, and Y. L. Li Xuezhikang, an Extract of Cholestin, Protects Endothelial Function Through Antiinflammatory and Lipid-Lowering Mechanisms in Patients With Coronary Heart Disease Circulation, August 24, 2004; 110(8): 915 - 920. [Abstract] [Full Text] [PDF]
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 M. Tobu, O. Iqbal, D. Fareed, M. Chatha, D. Hoppensteadt, V. Bansal, and J. Fareed Erythropoietin-Induced Thrombosis as a Result of Increased Inflammation and Thrombin Activatable Fibrinolytic Inhibitor Clinical and Applied Thrombosis/Hemostasis, July 1, 2004; 10(3): 225 - 232. [Abstract] [PDF]
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I. Jialal, S. Devaraj, and S. K. Venugopal C-Reactive Protein: Risk Marker or Mediator in Atherothrombosis? Hypertension, July 1, 2004; 44(1): 6 - 11. [Abstract] [Full Text] [PDF]
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K. Amann, M.-L. Gross, and E. Ritz Pathophysiology Underlying Accelerated Atherogenesis in Renal Disease: Closing in on the Target J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1664 - 1666. [Full Text] [PDF]
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 R. Tauman, A. Ivanenko, L. M. O'Brien, and D. Gozal Plasma C-Reactive Protein Levels Among Children With Sleep-Disordered Breathing Pediatrics, June 1, 2004; 113(6): e564 - e569. [Abstract] [Full Text]
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S. Verma, M. A. Kuliszewski, S.-H. Li, P. E. Szmitko, L. Zucco, C.-H. Wang, M. V. Badiwala, D. A.G. Mickle, R. D. Weisel, P. W.M. Fedak, et al. C-Reactive Protein Attenuates Endothelial Progenitor Cell Survival, Differentiation, and Function: Further Evidence of a Mechanistic Link Between C-Reactive Protein and Cardiovascular Disease Circulation, May 4, 2004; 109(17): 2058 - 2067. [Abstract] [Full Text] [PDF]
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S. Wan, A. P. C. Yim, J. L. Johnson, N. Shukla, G. D. Angelini, F. C. T. Smith, M. R. Dashwood, and J. Y. Jeremy The endothelin 1A receptor antagonist BSF 302146 is a potent inhibitor of neointimal and medial thickening in porcine saphenous vein-carotid artery interposition grafts J. Thorac. Cardiovasc. Surg., May 1, 2004; 127(5): 1317 - 1322. [Abstract] [Full Text] [PDF]
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S. Verma, P. E. Szmitko, and E. T.H. Yeh C-Reactive Protein: Structure Affects Function Circulation, April 27, 2004; 109(16): 1914 - 1917. [Full Text] [PDF]
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T. Khreiss, L. Jozsef, L. A. Potempa, and J. G. Filep Conformational Rearrangement in C-Reactive Protein Is Required for Proinflammatory Actions on Human Endothelial Cells Circulation, April 27, 2004; 109(16): 2016 - 2022. [Abstract] [Full Text] [PDF]
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R. Arroyo-Espliguero, P. Avanzas, J. Cosin-Sales, G. Aldama, C. Pizzi, and J. C. Kaski C-reactive protein elevation and disease activity in patients with coronary artery disease Eur. Heart J., March 1, 2004; 25(5): 401 - 408. [Abstract] [Full Text] [PDF]
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S.-H. Li, P. E. Szmitko, R. D. Weisel, C.-H. Wang, P. W.M. Fedak, R.-K. Li, D. A.G. Mickle, and S. Verma C-Reactive Protein Upregulates Complement-Inhibitory Factors in Endothelial Cells Circulation, February 24, 2004; 109(7): 833 - 836. [Abstract] [Full Text] [PDF]
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A. Paul, K. W.S. Ko, L. Li, V. Yechoor, M. A. McCrory, A. J. Szalai, and L. Chan C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, February 10, 2004; 109(5): 647 - 655. [Abstract] [Full Text] [PDF]
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G. J. Blake, N. Rifai, J. E. Buring, and P. M Ridker Blood Pressure, C-Reactive Protein, and Risk of Future Cardiovascular Events Circulation, December 16, 2003; 108(24): 2993 - 2999. [Abstract] [Full Text] [PDF]
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 H. D. Sesso, J. E. Buring, N. Rifai, G. J. Blake, J. M. Gaziano, and P. M. Ridker C-Reactive Protein and the Risk of Developing Hypertension JAMA, December 10, 2003; 290(22): 2945 - 2951. [Abstract] [Full Text] [PDF]
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S. Verma, M. V. Badiwala, R. D. Weisel, S.-H. Li, C.-H. Wang, P. W. M. Fedak, R.-K. Li, and D. A. G. Mickle C-reactive protein activates the nuclear factor-{kappa}B signal transduction pathway in saphenous vein endothelial cells: implications for atherosclerosis and restenosis J. Thorac. Cardiovasc. Surg., December 1, 2003; 126(6): 1886 - 1891. [Abstract] [Full Text] [PDF]
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S. Verma and P. E. Szmitko Coxibs and the endothelium J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1754 - 1756. [Full Text] [PDF]
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M. Schillinger, M. Exner, J. Amighi, W. Mlekusch, S. Sabeti, H. Rumpold, O. Wagner, and E. Minar Joint Effects of C-Reactive Protein and Glycated Hemoglobin in Predicting Future Cardiovascular Events of Patients With Advanced Atherosclerosis Circulation, November 11, 2003; 108(19): 2323 - 2328. [Abstract] [Full Text] [PDF]
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R. Arroyo-Espliguero, N. Mollichelli, P. Avanzas, E. Zouridakis, V. R Newey, D. K Nassiri, and J. C. Kaski Chronic inflammation and increased arterial stiffness in patients with cardiac syndrome X Eur. Heart J., November 2, 2003; 24(22): 2006 - 2011. [Abstract] [Full Text] [PDF]
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 G.M. Hirschfield and M.B. Pepys C-reactive protein and cardiovascular disease: new insights from an old molecule QJM, November 1, 2003; 96(11): 793 - 807. [Abstract] [Full Text] [PDF]
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 G. J. Blake and P. M. Ridker C-reactive protein: a surrogate risk marker or mediator of atherothrombosis? Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1250 - R1252. [Full Text] [PDF]
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S. Verma and E. T. H. Yeh C-reactive protein and atherothrombosis--Beyond a biomarker: an actual partaker of lesion formation Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1253 - R1256. [Full Text] [PDF]
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S. Verma, M. R. Buchanan, and T. J. Anderson Endothelial Function Testing as a Biomarker of Vascular Disease Circulation, October 28, 2003; 108(17): 2054 - 2059. [Full Text] [PDF]
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