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(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

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