Activated protein C promotes protease-activated receptor-1 cytoprotective signaling through SS-arrestin and dishevelled-2 scaffolds

摘要

A thin layer of endothelial cells lines the lumen of blood vessels to form a semipermeable barrier that separates blood components from the surrounding tissue. The integrity of this barrier plays important roles in blood pressure regulation, blood clot formation, and inflammation. The accumulation of "fat," also known as cholesterol, in blood vessels promotes endothelial cell dysfunction and is one of the many factors that initiate inflammation and an increased risk of blood clot formation or thrombosis. Thrombosis is mediated by thrombin, a key blood-clotting agent. These early events contribute to the progression of chronic cardiovascular disease and have been linked to decreased levels of activated Protein C (APC), a naturally occurring anticlotting and anti-inflammatory agent present in blood plasma (1). Human recombinant APC has been used as a drug for the treatment of severe sepsis, a life-threatening clinical condition resulting from uncontrolled inflammation and dysregulated blood clotting (1, 2). A recent mouse-model study has shown that an APC variant lacking anticlotting activity retains the capacity to reduce sepsis mortality, in part by stabilizing endothelial barrier function (3), suggesting that APC uses distinct mechanisms to fulfill its dual roles. APC functions as an anticlotting agent primarily by degrading blood proteins that facilitate thrombin generation. However, the processes by which APC functions as an anti-inflammatory and cytoprotective agent on cells remains poorly understood. Our study identifies a distinct signaling cascade essential for APC's beneficial effects on endothelial barrier function and provides further insights into the mechanisms underlying APC's anti-inflammatory activities, which present a potential new therapeutic target for treating inflammatory conditions.