# Activated Protein C in Acute Injury

> **NIH VA I01** · JAMES A. HALEY VA MEDICAL CENTER · 2023 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10475352
- **Project number:** 1I01CX002406-01A1
- **Recipient organization:** JAMES A. HALEY VA MEDICAL CENTER
- **Principal Investigator:** Ji Li
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-11-01 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475352

## Citation

> US National Institutes of Health, RePORTER application 10475352, Activated Protein C in Acute Injury (1I01CX002406-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10475352. Licensed CC0.

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