This Article Full Text Full Text (PDF) All Versions of this Article: 25/10/2216    most recent 01.ATV.0000183718.62409.eav1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Singh, U. Articles by Jialal, I. Search for Related Content PubMed PubMed Citation Articles by Singh, U. Articles by Jialal, I. Related Collections Pathophysiology Thrombosis risk factors Coagulation and fibronolysis

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2216.)
© 2005 American Heart Association, Inc.

Thrombosis

C-Reactive Protein Decreases Tissue Plasminogen Activator Activity in Human Aortic Endothelial Cells

Evidence that C-Reactive Protein Is a Procoagulant

Uma Singh; Sridevi Devaraj; Ishwarlal Jialal

From the Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis Medical Center, Sacramento, Calif.

Correspondence to Ishwarlal Jialal, Director of the Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis Medical Center, 4635, 2nd Ave, Sacramento, CA 95817.E-mail ishwarlal.jialal{at}ucdmc.ucdavis.edu

Abstract

Objective— C-reactive protein (CRP) can promote atherothrombosis by decreasing endothelial nitric oxide synthase and prostacyclin, and by stimulating both plasminogen activator inhibitor-1 in endothelial cells and tissue factor in mononuclear cells. Plasminogen activator-1, a marker of fibrinolysis, is the primary inhibitor of tissue plasminogen activator (tPA). Thus, we tested the effect of CRP on tPA in human aortic endothelial cells.

Methods and Results— Incubation of human aortic endothelial cells with CRP (12.5 µg/mL) significantly decreased tPA antigen and activity. Adenyl cyclase inhibitors, an endothelin receptor antagonist, superoxide dismutase, and a nitric oxide donor failed to reverse the effect of CRP on tPA. CRP increased interleukin (IL)-1ß and tumor necrosis factor (TNF)-. Neutralization of both IL-1ß and TNF reversed the inhibition of tPA by CRP. Furthermore, in volunteers that have high CRP levels, euglobulin clot lysis time was significantly increased compared with those that have low CRP levels, providing further evidence that high CRP levels are associated with a procoagulant state.

Conclusions— CRP inhibits tPA activity via generation of proinflammatory cytokines (IL-1ß and TNF). This study provides additional novel data that CRP is a procoagulant and has implications for atherothrombosis.

C-reactive protein (CRP) treatment of human aortic endothelial cells significantly decreased secreted tissue plasminogen activator (tPA) antigen and activity. CRP treatment increased IL-1ß and TNF, and neutralization of these reversed CRP-mediated inhibition of tPA. CRP inhibits tPA activity via generation of proinflammatory cytokines, providing further evidence that CRP is a procoagulant.

Key Words: inflammation • endothelial cells • C-reactive protein • tissue plasminogen activator • procoagulant

This article has been cited by other articles:

				S. Devaraj, U. Singh, and I. Jialal The Evolving Role of C-Reactive Protein in Atherothrombosis Clin. Chem., February 1, 2009; 55(2): 229 - 238. [Abstract] [Full Text] [PDF]

				H. Teoh, A. Quan, and S. Verma Does C-reactive protein predict saphenous vein graft patency? J. Thorac. Cardiovasc. Surg., August 1, 2007; 134(2): 277 - 279. [Full Text] [PDF]

				E. Grad, M. Golomb, I. Mor-Yosef, N. Koroukhov, C. Lotan, E. R. Edelman, and H. D. Danenberg Transgenic expression of human C-reactive protein suppresses endothelial nitric oxide synthase expression and bioactivity after vascular injury Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H489 - H495. [Abstract] [Full Text] [PDF]

				P. E. Szmitko and S. Verma C-Reactive Protein and Reendothelialization: NO Involvement Circ. Res., May 25, 2007; 100(10): 1405 - 1407. [Full Text] [PDF]

				E. A. Gabriel, R. F. Locali, C. C. Romano, A. J. d. S. Duarte, J. H. Palma, and E. Buffolo Analysis of the inflammatory response in endovascular treatment of aortic aneurysms Eur. J. Cardiothorac. Surg., March 1, 2007; 31(3): 406 - 412. [Abstract] [Full Text] [PDF]

				M. R. Dasu, S. Devaraj, T. W. Du Clos, and I. Jialal The biological effects of CRP are not attributable to endotoxin contamination: evidence from TLR4 knockdown human aortic endothelial cells J. Lipid Res., March 1, 2007; 48(3): 509 - 512. [Abstract] [Full Text] [PDF]

				U. Singh, S. Devaraj, M. R. Dasu, D. Ciobanu, J. Reusch, and I. Jialal C-Reactive Protein Decreases Interleukin-10 Secretion in Activated Human Monocyte-Derived Macrophages via Inhibition of Cyclic AMP Production Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2469 - 2475. [Abstract] [Full Text] [PDF]

				H. Fujii, S.-H. Li, P. E. Szmitko, P. W.M. Fedak, and S. Verma C-Reactive Protein Alters Antioxidant Defenses and Promotes Apoptosis in Endothelial Progenitor Cells Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2476 - 2482. [Abstract] [Full Text] [PDF]

				V. Bhatia, A. Chaudhuri, R. Tomar, S. Dhindsa, H. Ghanim, and P. Dandona Low Testosterone and High C-Reactive Protein Concentrations Predict Low Hematocrit in Type 2 Diabetes Diabetes Care, October 1, 2006; 29(10): 2289 - 2294. [Abstract] [Full Text] [PDF]

				Y. Zhong, S.-H. Li, S.-M. Liu, P. E. Szmitko, X.-Q. He, P. W.M. Fedak, and S. Verma C-Reactive Protein Upregulates Receptor for Advanced Glycation End Products Expression in Human Endothelial Cells Hypertension, September 1, 2006; 48(3): 504 - 511. [Abstract] [Full Text] [PDF]

				E. Paffen and M. P.M. deMaat C-reactive protein in atherosclerosis: A causal factor? Cardiovasc Res, July 1, 2006; 71(1): 30 - 39. [Abstract] [Full Text] [PDF]

				B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, I. Jialal, B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, and I. Jialal The Verdict Is Still Out Circulation, May 2, 2006; 113(17): 2128 - 2151. [Full Text] [PDF]

				I. Jialal, S. Devaraj, and U. Singh C-Reactive Protein and the Vascular Endothelium: Implications for Plaque Instability J. Am. Coll. Cardiol., April 4, 2006; 47(7): 1379 - 1381. [Full Text] [PDF]