Scientific Report 2007

Molecular and Experimental Medicine

Protein C (PC), a serine protease zymogen, and its enzymatically active derivative, activated protein C (APC), are normal components of human blood. Discovery of the pathologic effects of hereditary PC deficiency in humans at Scripps Research helped lead to clinical trials that resulted in approvals of both PC and APC as drugs by the Food and Drug Administration. The decrease in mortality in patients with severe sepsis treated with recombinant APC gave impetus to new directions for basic and preclinical research on APC. A, APC is generated by the enzymatic action of thrombin (IIa) on endothelial cell membranes, where the endothelial PC receptor (EPCR) and thrombomodulin (TM) reversibly bind the reaction components. B, Dissociation of APC from EPCR (A) allows expression of APC anticoagulant activity involving proteolytic inactivation of 2 blood clotting cofactor proteins, Va (fV_a) and VIIIa (fVIII_a), by APC to yield the inactivated cofactors fV_i and fVIII_i. C, In contrast, binding of APC to EPCR on cells mediates expression of the multiple direct cellular activities of APC that require the 2 cellular receptors EPCR and protease-activated receptor 1 (PAR-1). Because of its pleiotropic activities, APC not only is useful in treatement of sepsis but also is promising as a potential treatment of other complex conditions such as thrombosis, ischemic stroke, and chronic neurodegenerative disorders. This figure was orignally published in Blood. Mosnier, L.O., Zlokovic, B.V., Griffin, J.H. The cytoprotective protein C pathway. Blood 109: 3161, 2007. ©The American Society of Hematology. Work done by Laurent Mosnier, Ph.D., research associate, in the laboratory of John H. Griffin, Ph.D., professor.