The cytoprotective protein C pathway.
Protein C is best known for its mild deficiency associated with venous thrombosis risk and severe deficiency associated with neonatal purpura fulminans. Activated protein C (APC) anticoagulant activity involves proteolytic inactivation of factors Va and VIIIa, and APC resistance is often caused by factor V Leiden. Less known is the clinical success of APC in reducing mortality in severe sepsis patients (PROWESS trial) that gave impetus to new directions for basic and preclinical research on APC. This review summarizes insights gleaned from recent in vitro and in vivo studies of the direct cytoprotective effects of APC that include beneficial alterations in gene expression profiles, anti-inflammatory actions, antiapoptotic activities, and stabilization of endothelial barriers. APC's cytoprotection requires its receptor, endothelial cell protein C receptor, and protease-activated receptor-1. Because of its pleiotropic activities, APC has potential roles in the treatment of complex disorders, including sepsis, thrombosis, and ischemic stroke. Although much about molecular mechanisms for APC's effects on cells remains unclear, it is clear that APC's structural features mediating anticoagulant actions and related bleeding risks are distinct from those mediating cytoprotective actions, suggesting the possibility of developing APC variants with an improved profile for the ratio of cytoprotective to anticoagulant actions.
Mosnier
Laurent O
LO
Department of Molecular and Experimental Medicine (MEM-180), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA.
Zlokovic
Berislav V
BV
Griffin
John H
JH
D020016:Activated Protein C Resistance / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000378:metabolism; D019610:Cytoprotection; D000074283:Endothelial Protein C Receptor; D004727:Endothelium; D005786:Gene Expression Regulation; D006470:Hemorrhage / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D018919:Neovascularization, Physiologic; D011486:Protein C / Q000378:metabolism*; D020151:Protein C Deficiency / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012307:Risk Factors; D018805:Sepsis / Q000378:metabolism; D020521:Stroke / Q000378:metabolism; D020246:Venous Thrombosis / Q000378:metabolism; D014945:Wound Healing
D015703:Antigens, CD; D001779:Blood Coagulation Factors; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D011486:Protein C; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface