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

ABSTRACT: 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.The objective of this study was to understand the mechanism of the APC-mediated cardioprotection against ischemic injury.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.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 TNF? and IL-6 in vivo by attenuating the ischemia/reperfusion-induced JNK and NF-?B signaling pathways.APC exerts a cardioprotective function in ischemic/reperfusion injury through modulation of AMPK, NF-?B and JNK signaling pathways.

SUBMITTER: Wang J 

PROVIDER: S-EPMC3129410 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature