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

Uma Singh1, Sridevi Devaraj, Ishwarlal Jialal

  • 1Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis Medical Center, Sacramento, CA 95817, USA.

Arteriosclerosis, Thrombosis, and Vascular Biology
|August 27, 2005
PubMed

Insights

C-reactive protein (CRP) inhibits tissue plasminogen activator (tPA) activity by increasing inflammatory cytokines, contributing to a procoagulant state and promoting atherothrombosis.

Area of Science:

  • Cardiovascular Biology
  • Inflammation Research
  • Thrombosis and Hemostasis

Background:

  • C-reactive protein (CRP) is implicated in atherothrombosis.
  • CRP may influence endothelial function and coagulation pathways.
  • The precise mechanisms by which CRP affects fibrinolysis are not fully elucidated.

Purpose of the Study:

  • To investigate the effect of CRP on tissue plasminogen activator (tPA) in human aortic endothelial cells.
  • To determine the role of inflammatory cytokines in CRP-mediated tPA inhibition.
  • To assess the association between CRP levels and the procoagulant state in vivo.

Main Methods:

  • Human aortic endothelial cells were incubated with varying concentrations of CRP.
  • tPA antigen and activity were measured.
  • The effects of various inhibitors and cytokine neutralization on CRP-induced tPA changes were examined.
  • Euglobulin clot lysis time was measured in volunteers with high and low CRP levels.

Main Results:

  • CRP significantly decreased tPA antigen and activity in endothelial cells at concentrations ≥12.5 μg/mL.
  • Inhibitors of adenyl cyclase, endothelin receptors, superoxide dismutase, and nitric oxide donors did not reverse CRP's effect on tPA.
  • CRP increased interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels.
  • Neutralization of IL-1β and TNF-α reversed CRP-induced tPA inhibition.
  • Individuals with high CRP levels exhibited increased euglobulin clot lysis time, indicating a procoagulant state.

Conclusions:

  • CRP inhibits tPA activity through the generation of pro-inflammatory cytokines IL-1β and TNF-α.
  • This mechanism contributes to a procoagulant state.
  • CRP plays a significant role in promoting atherothrombosis.
Abstract

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