Key result
Thrombin inhibited HMGB1-mediated proinflammatory signaling responses, including TNF-α and IL-6 induction, hyperpermeability, and leukocyte adhesion, in human endothelial cells when EPCR was occupied by protein C.
p-value: p=<0.01
Thrombin exerts anti-inflammatory effects against HMGB1-mediated signaling in endothelial cells when EPCR is occupied by protein C, suggesting its PAR-1-dependent proinflammatory effects may not apply to normal vessels in vivo.
May inform endothelial inflammation models; leaves open whether thrombin's PAR-1 effects differ in normal versus diseased human vessels.
High mobility group box 1 (HMGB1) is involved in the pathogenesis of vascular diseases. Unlike activated protein C (APC), the activation of PAR-1 by thrombin is known to elicit proinflammatory responses. To determine whether the occupancy of EPCR by the Gla-domain of APC is responsible for the PAR-1-dependent antiinflammatory activity of the protease, we pretreated HUVECs with the PC zymogen and then activated PAR-1 with thrombin. It was found that thrombin down-regulates the HMGB1-mediated induction of both TNF-α and IL-6 and inhibits the activation of both p38 MAPK and NF-κB in HUVECs pretreated with PC. Furthermore, thrombin inhibited HMGB1-mediated hyperpermeability and leukocyte adhesion/migration by inhibiting the expression of cell adhesion molecules in HUVECs if EPCR was occupied. Collectively, these results suggest the concept that thrombin can initiate proinflammatory responses in vascular endothelial cells through the activation of PAR-1 may not hold true for normal vessels expressing EPCR under in vivo conditions.
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Bae et al. (2013) studied Vascular inflammation (in vitro model). Thrombin and Protein C (PC-S195A) vs. HMGB1 or LPS alone was evaluated on HMGB1-mediated proinflammatory signaling responses (TNF-α, IL-6, p38 MAPK, NF-κB, permeability, CAM expression) (p=<0.01). Thrombin inhibited HMGB1-mediated proinflammatory signaling responses, including TNF-α and IL-6 induction, hyperpermeability, and leukocyte adhesion, in human endothelial cells when EPCR was occupied by protein C.
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