Activated protein C and ischemic stroke

Objective. To summarize clinical observations, animal model experimentation, and in vitro studies that advance knowledge of the protein C system, including activated protein C (APC), in the setting of ischemic stroke. Data Source. Narrative review of selected published primary basic and clinical literature from MEDLINE for 2000-2003. Data Synthesis. Low levels of plasma APC and a poor response to APC in clotting assays may be markers or risk factors for ischemic stroke. Ischemia during routine endarterectomy causes APC generation in the affected region of the human brain. The prospective epidemiologic Atherosclerosis Risk in Communities (ARIC) study reported that plasma protein C may be protective for ischemic stroke. In murine models of focal cerebral ischemia, APC provided remarkable anti-inflammatory and neuroprotective effects in vivo and increased survival at 24 hrs. Recent in vitro and in vivo studies provide remarkable insights into mechanisms of the neuroprotective activities of APC. Independent of its wellknown anticoagulant activity, APC acts directly on cells and alters gene expression profiles, inhibits apoptosis, and down-regulates inflammation. These effects require protease-activated receptor-1 and the endothelial protein C receptor. In an in vitro model involving hypoxia-induced apoptosis of human brain endothelial cells, protease-activated receptor-1 and endothelial protein C receptor were required, for APC to exert its anti-apoptotic effects. In these cells, APC blunts hypoxia-induced increases in p53 messenger RNA and protein, reduces pro-apoptotic Bax, and increases anti-apoptotic Bcl-2, thereby inhibiting mitochondrial-dependent apoptosis. Murine ischemic stroke model studies have provided in vivo evidence for the physiologic roles of protease-activated receptor-1 and endothelial protein C receptor in the neuroprotective activities of APC. Because the low doses required for recombinant murine APC to provide neuroprotection do not cause observable anticoagulant effects, the in vivo neuroprotective action of APC seems, at least in part, to be independent of its anticoagulant activity and is likely to involve its anti-apoptotic activity. Conclusions. There is compelling evidence that ischemic stroke is an attractive target for therapy with APC.