Thrombin‐bound dabigatran modulates protease‐activated receptor‐1 expression (1066.14)

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Thrombin is the key effector protease of the coagulation cascade and major drug target for anticoagulation therapy. Dabigatran is a synthetic oral direct thrombin inhibitor and is currently being used for multiple thromboembolic disease indications. Dabigatran binds with high affinity to free and clot‐bound thrombin, suggesting that dabigatran‐bound thrombin may modulate expression and activity of protease‐activated receptor‐1 (PAR1), the major effector of thrombin signaling. The N‐terminal LDPR‐S sequence of PAR1 is recognized by thrombin’s active site, which is inhibited by dabigatran. However, a second interaction occurs between thrombin’s exosite‐I, which is spatially separated from the active site, and the “hirudin”‐like sequence present in the N‐terminus of PAR1. In this study, we examined whether thrombin‐bound dabigatran regulates PAR1 expression and function using culture human endothelial cells and other cell models. As expected, we found that dabigatran inhibited thrombin cleavage of PAR1, blocked activated PAR1 internalization and G protein signaling. Intriguingly, however, prolonged incubation of cells with dabigatran‐bound thrombin resulted in elevated expression of PAR1 at the cell surface. These findings suggest that thrombin‐bound dabigratan modulates PAR1 expression and future studies are directed towards understanding the biological consequences of this effect.Grant Funding Source: Supported by Boehringer Ingelheim International Collaborative Research Agreement and NIH/NIGMS R01