Regulation of endothelial function by coagulation proteases in sepsis

Excerpt

Thrombin and activated protein C (aPC) are two pleiotropic proteases whose opposing functions in hemostasis and endothelial function are dysregulated during sepsis. Exogenous supplementation of aPC, the ligand for endothelial protein C receptor (EPCR), is the only known therapeutic shown to reduce mortality in severe septic patients. Paradoxically, both thrombin and aPC signal the endothelium via the same receptor, protease-activated receptor-1 (PAR-1), by cleaving its N-terminus to produce an identical tethered ligand, yet result in opposing signaling networks. Once activated, PAR-1 triggers at least three separate signaling pathways (Gi, Gq, G13) and it is the relative contribution of each pathway that determines the endothelial response. Thrombin is a potent proinflammatory, endothelial barrier disruptive agonist, while aPC induces an anti-inflammatory and barrier protective phenotype, thought to be important to its therapeutic mechanism. We hypothesized that when bound to its ligand, aPC, EPCR functionally dimerizes with activated PAR-1, thereby altering its specificity for Gq, an important mediator of proinflammatory pathways in endothelial cells. …