Concentration dependent dual effect of thrombin in endothelial cells via Par-1 and Pi3 Kinase

J Cell Physiol. 2009 Jun;219(3):744-51. doi: 10.1002/jcp.21718.


Disruption of endothelial barrier is a critical pathophysiological factor in inflammation. Thrombin exerts a variety of cellular effects including inflammation and apoptosis through activation of the protease activated receptors (PARs). The activation of PAR-1 by thrombin is known to have a bimodal effect in endothelial cell permeability with a low concentration (pM levels) eliciting a barrier protective and a high concentration (nM levels) eliciting a barrier disruptive response. It is not known whether this PAR-1-dependent activity of thrombin is a unique phenomenon specific for the in vitro assay or it is part of a general anti-inflammatory effect of low concentrations of thrombin that may have a physiological relevance. Here, we report that low concentrations of thrombin or of PAR-1 agonist peptide induced significant anti-inflammatory activities. However, relatively high concentration of thrombin or of PAR-1 agonist peptide showed pro-inflammatory activities. By using function-blocking anti-PAR-1 antibodies and PI3 kinase inhibitor, we show that the direct anti-inflammatory effects of low concentrations of thrombin are dependent on the activation of PAR-1 and PI3 kinase. These results suggest a role for cross communication between PAR-1 activation and PI3 kinase pathway in mediating the cytoprotective effects of low concentrations of thrombin in the cytokine-stimulated endothelial cells. J. Cell. Physiol. 219: 744-751, 2009. (c) 2009 Wiley-Liss, Inc.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Cell Adhesion / drug effects
  • Cell Adhesion Molecules / metabolism
  • Cell Membrane Permeability / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Endothelial Cells / physiology
  • Humans
  • In Vitro Techniques
  • Neutrophils / drug effects
  • Oligopeptides / administration & dosage
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Receptor, PAR-1 / agonists
  • Receptor, PAR-1 / metabolism*
  • Thrombin / administration & dosage*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cell Adhesion Molecules
  • Oligopeptides
  • Receptor, PAR-1
  • Tumor Necrosis Factor-alpha
  • threonyl-phenylalanyl-leucyl-leucyl-arginyl-asparagine
  • Phosphatidylinositol 3-Kinases
  • Thrombin