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Background:Activated Protein C (APC) is a natural anticoagulant protein, with recently discovered anti-inflammatory and anti-apoptotic effects.We recently unveiled that APC can limit cardiac ischemia/reperfusion (I/R) injury and is independent of its anticoagulant activity.Modulation of the energy substrate metabolism may constitute a novel therapeutic intervention in the ischemic heart.AMP-activated protein kinase (AMPK) has emerged as a key regulator of favorable metabolic signaling pathways in response to myocardial ischemia.Here, we elucidate the signaling pathways by which APC mediates its salutary actions and characterize the role of APCs modulation of substrate metabolism in its cardioprotective effect on I/R injury.