C-reactive protein decreases tissue plasminogen activator activity in human aortic endothelial cells: evidence that C-reactive protein is a procoagulant.
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.


RESULTS
Incubation of human aortic endothelial cells with CRP (> or =12.5 microg/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)-1beta and tumor necrosis factor (TNF)-alpha. Neutralization of both IL-1beta and TNFalpha 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-1beta and TNFalpha). This study provides additional novel data that CRP is a procoagulant and has implications for atherothrombosis.
Singh
Uma
U
Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis Medical Center, Sacramento, CA 95817, USA.
Devaraj
Sridevi
S
Jialal
Ishwarlal
I
D001011:Aorta / Q000166:cytology; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology; D001777:Blood Coagulation / Q000502:physiology; D002097:C-Reactive Protein / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D012333:RNA, Messenger / Q000032:analysis; D013927:Thrombosis / Q000378:metabolism* / Q000503:physiopathology*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D002097:C-Reactive Protein; D010959:Tissue Plasminogen Activator