Activated Protein C in Acute Injury

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Cardiovascular disease is the leading cause of death among Veterans and ischemic heart disease-related congestive heart failure is among the most common conditions for hospitalization. With aging along with prevalent risk factors such as diabetes, chronic obstructive pulmonary disease, obesity, and hypertension, ischemic heart disease is a cardiac malady that is linked to a variety of pathologies, such as coronary arteriosclerosis and coronary thrombosis. Activated protein C (APC) was first identified as a natural anticoagulant enzyme. Besides its anticoagulant activity, APC exerts cytoprotective effects such as anti- inflammatory and anti-apoptosis. We revealed that APC activity was decreased in the heart during ischemia and reperfusion (I/R), and APC receptor EPCR was impaired in aging. Intriguingly, administration of APC can stabilize EPCR from shedding by I/R and strengthen cardiac tolerance to ischemic insults in aging. However, the mechanism involved in cardioprotection stimulated by APC is still unclear. The objective of this project is to illustrate the mechanism by which APC mediates cardioprotection against ischemic injury, and characterize the APC signaling in myocardial infarct veteran patients versus healthy veterans. AMP-activated protein kinase (AMPK), cardioprotective signaling, was activated in APC treated mouse heart. Moreover, I/R-induced stress-activated protein kinase (SAPK/JNK) signaling was attenuated by APC treatment. We hypothesize that APC protects against myocardial ischemic injury by triggering crucial signaling pathways to modulate substrates metabolism and reducing inflammatory response under ischemic stress. Two specific aims will be addressed to test the hypothesis: (1) to characterize the role of APC derivatives in cardiac inflammatory response during reperfusion injury in aging; (2) to determine the mechanisms by which APC modulates glucose metabolism and redox homeostasis that responsible for the inflammatory response in the ischemic heart. APC signaling could be impaired in myocardial infarction Veteran patients versus healthy Veterans. We will elucidate which domains of APC is critical for its cardioprotection against I/R injury, which will provide evidence that recombinant APC can be used for therapy of ischemic heart disease without the risk of bleeding. VETERANS HEALTH RELEVANCE: Ischemic heart disease, which affects approximately one million Americans each year, is most often caused by ischemic insults leading to myocardial damage. This grant pursues studies to explore the signaling mechanisms underlying APC’s role in inhibiting inflammation thereby modulating the heart’s response to ischemic insults. The results could lead to novel therapeutic strategies aimed at limiting cardiac damage for myocardial infarction Veteran patients.