Activated protein C: a potential cardioprotective factor against ischemic injury during ischemia/reperfusion

Activated protein C (APC) is a vitamin-K dependent natural anticoagulant protein. With its function in blood clotting reaction, APC can reduce the risk of venous thrombosis to prevent ischemic disease. A number of in vivo and in vitro studies over the past few decades have revealed that APC also exerted cytoprotective effects to decrease the mortality caused by endotoxin, sepsis, and brain ischemic stroke. The direct cytoprotective role requires APC binding to the endothelial protein C receptor (EPCR) and activating protease activated receptor-1 (PAR-1). It is now believed that the beneficial characters of APC are partially independent from its anticoagulant activity, though more studies need to be done to demonstrate the exact molecular mechanism. In this review, we have linked the cytoprotective effects of APC including the anti-inflammatory and anti-apoptosis activities to myocardial ischemic injury caused by cardiac ischemia reperfusion. Specifically, we have tried to combine the potential signaling pathways initiated by APC with the well-known adaptive signaling such as AMP-activated protein kinase (AMPK), PI3K/Akt and ERK/MAPK pathways that contribute to the cardioprotection against myocardial ischemia injury. We speculate that APC protects against cardiac ischemia injury via triggering crucial cardioprotective signaling pathways, and these effects are mostly associated with its cytoprotective activity but independent on its anticoagulant activity.