Apolipoprotein A-I enhances activated protein C cytoprotective activity.

High-density lipoprotein and apolipoprotein A-I enhance activated protein C cytoprotective activity. High-density lipoprotein and apolipoprotein A-I significantly increase the rate at which activated protein C degrades cytotoxic extracellular histones.

Activated protein C β-glycoform promotes enhanced noncanonical PAR1 proteolysis and superior resistance to ischemic injury.

Activated protein C (APC) is an anticoagulant protease that initiates cell signaling via protease-activated receptor 1 (PAR1) to regulate vascular integrity and inflammatory response. In this study, a recombinant APC variant (APC(N329Q)) mimicking the naturally occurring APC-β plasma glycoform was found to exhibit superior PAR1 proteolysis at a cleavage site that selectively mediates cytoprotective signaling. APC(N329Q) also enhanced integrin αMβ2-dependent PAR1 proteolysis to exert significantly improved antiinflammatory activity on macrophages compared with wild-type APC.

Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from lipopolysaccharide-stimulated myeloid cells.

Vitamin K-dependent proteases generated in response to vascular injury and infection enable fibrin clot formation, but also trigger distinct immuno-regulatory signaling pathways on myeloid cells. Factor Xa, a protease crucial for blood coagulation, also induces protease-activated, receptor-dependent cell signaling. Factor Xa can bind both monocytes and macrophages, but whether factor Xa-dependent signaling stimulates or suppresses myeloid cell cytokine production in response to Toll-like receptor activation is not known.

Elucidating the role of carbohydrate determinants in regulating hemostasis: insights and opportunities.

Recent improvement in modern analytical technologies has stimulated an explosive growth in the study of glycobiology. In turn, this has lead to a richer understanding of the crucial role of N- and O-linked carbohydrates in dictating the properties of the proteins to which they are attached and, in particular, their centrality in the control of protein synthesis, longevity, and activity. Given their importance, it is unsurprising that both gross and subtle defects in glycosylation often contribute to human disease pathology.

The endothelial cell protein C receptor: cell surface conductor of cytoprotective coagulation factor signaling.

Increasing evidence links blood coagulation proteins with the regulation of acute and chronic inflammatory disease. Of particular interest are vitamin K-dependent proteases, which are generated as a hemostatic response to vascular injury, but can also initiate signal transduction via interactions with vascular receptors. The endothelial cell protein C receptor (EPCR) is a multi-ligand vitamin K-dependent protein receptor for zymogen and activated forms of plasma protein C and factor VII.

Activated protein C N-linked glycans modulate cytoprotective signaling function on endothelial cells.

Activated protein C (APC) has potent anticoagulant and anti-inflammatory properties that limit clot formation, inhibit apoptosis, and protect vascular endothelial cell barrier integrity. In this study, the role of N-linked glycans in modulating APC endothelial cytoprotective signaling via endothelial cell protein C receptor/protease-activated receptor 1 (PAR1) was investigated. Enzymatic digestion of APC N-linked glycans (PNG-APC) decreased the APC concentration required to achieve half-maximal inhibition of thrombin-induced endothelial cell barrier permeability by 6-fold.