Key result
When EPCR is occupied by protein C, thrombin cleavage of PAR-1 initiates anti-inflammatory responses, activating Rac1 and inhibiting RhoA and NF-kappaB signaling in vascular endothelial cells.
Thrombin initiates anti-inflammatory responses via PAR-1 cleavage in vascular endothelial cells when EPCR is ligated by protein C, inhibiting RhoA and NF-kappaB pathways.
May guide EPCR-targeted endothelial protection strategies; leaves open human translation from animal models.
The occupancy of endothelial protein C receptor (EPCR) by protein C switches the protease activated receptor 1 (PAR-1)-dependent signalling specificity of thrombin from a permeability enhancing to a barrier protective response in vascular endothelial cells. In this study, the modulatory effects of thrombin and thrombin receptor agonist peptides (TRAP) on tumour necrosis factor (TNF)-alpha-stimulated HUVECs in the absence and presence of the catalytically inactive protein C-S195A were evaluated by monitoring the expression of cell surface adhesion molecules (VCAM-1, ICAM-1 and E-selectin), adhesion of freshly isolated neutrophils to cytokine-stimulated endothelial cells, regulation of the Rho family of small GTPases and the activation of nuclear factor-kappaB (NF-kappaB) pathway. The analysis of results indicate that both thrombin and TRAP initiate proinflammatory responses in endothelial cells, thus neither PAR-1 agonist influenced the proinflammatory effects of TNF-alpha in the absence of the protein C mutant. Interestingly, however, the occupancy of EPCR by the protein C mutant switched the PAR-1-dependent signaling specificity of thrombin, thus leading to thrombin inhibition of the expression of all three adhesion molecules as well as the binding of neutrophils to TNF-alpha-activated endothelial cells. Furthermore, similar to activated protein C, both thrombin and TRAP activated Rac1 and inhibited the activation of RhoA and NF-kappaB pathways in response to TNF-alpha in cells pretreated with protein C-S195A. Based on these results we conclude that when EPCR is ligated by protein C, the cleavage of PAR-1 by thrombin initiates antiinflammatory responses, thus leading to activation of Rac1 and inhibition of RhoA and NF-kappaB signalling cascades in vascular endothelial cells.
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Bae et al. (2009) studied this question. Thrombin and TRAP in the presence of protein C-S195A vs. Absence of protein C mutant was evaluated on Expression of cell surface adhesion molecules, neutrophil adhesion, regulation of Rho GTPases, and NF-kappaB pathway activation. When EPCR is occupied by protein C, thrombin cleavage of PAR-1 initiates anti-inflammatory responses, activating Rac1 and inhibiting RhoA and NF-kappaB signaling in vascular endothelial cells.
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