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J Thromb Haemost. 2011 Jul;9(7):1308-17. doi: 10.1111/j.1538-7836.2011.04331.x.

Activated protein C protects against myocardial ischemic/reperfusion injury through AMP-activated protein kinase signaling.

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  • 1Department of Pharmacology and Toxicology, University at Buffalo-SUNY, Buffalo, NY, USA.

Abstract

BACKGROUND:

Activated protein C (APC) is a vitamin K-dependent plasma serine protease that down-regulates clotting and inflammatory pathways. It is known that APC exerts a cardioprotective effect by decreasing apoptosis of cardiomyocytes and inhibiting expression of inflammatory mediators after myocardial ischemia.

OBJECTIVES:

The objective of this study was to understand the mechanism of the APC-mediated cardioprotection against ischemic injury.

METHODS:

Cardioprotective activities of wild-type APC and two derivatives, having either dramatically reduced anticoagulant activity or lacking signaling activity, were monitored in an acute ischemia/reperfusion injury model in which the left anterior descending coronary artery (LAD) was occluded.

RESULTS:

APC reduced the myocardial infarct size by a mechanism that was largely independent of its anticoagulant activity. Thus, the non-anticoagulant APC-2Cys mutant, but not the non-signaling APC-E170A mutant, attenuated myocardial infarct size by EPCR and PAR-1-dependent mechanisms. Further studies revealed that APC acts directly on cardiomyocytes to stimulate the AMP-activated protein kinase (AMPK) signaling pathway. The activation of AMPK by APC ameliorated the post-ischemic cardiac dysfunction in isolated perfused mouse hearts. Moreover, both APC and APC-2Cys inhibited production of TNFα and IL-6 in vivo by attenuating the ischemia/reperfusion-induced JNK and NF-κB signaling pathways.

CONCLUSIONS:

APC exerts a cardioprotective function in ischemic/reperfusion injury through modulation of AMPK, NF-κB and JNK signaling pathways.

© 2011 International Society on Thrombosis and Haemostasis.

PMID:
21535395
[PubMed - indexed for MEDLINE]
PMCID:
PMC3129410
Free PMC Article

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