Concentration Dependent Dual Effect of Thrombin in Endothelial Cells Via Par-1 and Pi3 Kinase

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-I 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-I-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-I agonist peptide induced significant anti-inflammatory activities. However, relatively high concentration of thrombin or of PAR-I agonist peptide showed pro-inflammatory activities. By using function-blocking anti-PAR-I 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-I and PI3 kinase. These results suggest a role for cross communication between PAR-I 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.