Activated Protein C Protects Against Myocardial Ischemia/ Reperfusion Injury via Inhibition of Apoptosis and Inflammation

Abstract

Objective-In spite of major advances in reperfusion therapy for patients presenting with acute coronary syndrome, long-term morbidity is still substantial. A limitation of initial treatment of myocardial ischemia is the lack of prevention of ischemia/reperfusion (I/R) injury. Activated protein C (APC), a crucial mediator in the coagulation process, plays a prominent role in the crosstalk between coagulation and inflammation and provides cytoprotective effects via inhibition of apoptosis and inflammation in several human and animal studies. Methods and Results-APC was administered in an animal model for myocardial I/R. APC largely inhibited early myocardial I/R injury after varying reperfusion times, an effect that was absent on administration of heparin, a nonspecific anticoagulant agent. The protective effects of APC were absent in case of absence or blockade of protease activated receptor-1 (PAR-1), indicating a critical role for PAR-1 in this process. Furthermore, we showed a strong antiapoptotic effect of APC in the early phase of reperfusion combined with an antiinflammatory effect at an early stage (IL-6), as well as at a later stage (leukocyte infiltration). Conclusions-APC

Adipose-derived regenerative cells exert beneficial effects on systemic responses following myocardial ischemia/reperfusion

“…Inhibition of factor Xa has been shown to reduce inflammation in a model of acute myocardial I/R injury [21]. This protective effect has been associated with phosphorylation of ERK1/2 and STAT-3 [22,23]. These results support the hypothesis that reduction of factor Xa expression in the liver may be one of the cardiprotective effects caused by ADRC administration.…”

Activated protein C: biased for translation

“…In multiple preclinical models of cardiac I/R injury, APC has demonstrated significant benefits. [59][60][61][62][63] PAR1 and EPCR were required for the in vivo beneficial effects of APC in murine coronary I/R injury. 63 Despite multiple studies showing reduction of coronary I/R injury, it remains to be established how long after ischemia onset APC may be beneficial or what receptors, in addition to PAR1, mediate APC's cardioprotection.…”

Factor VII activating protease (FSAP) regulates the expression of inflammatory genes in vascular smooth muscle and endothelial cells

“…Indeed it was shown that APC protects the heart from ischemia reperfusion (I/R) injury through PAR1 signaling. In the early inflammatory phase, APC decreases apoptosis, secretion of the pro-inflammatory cytokine IL-6 and leukocyte infiltration 142 . Activation of PAR2 also protects the heart from I/R injury by decreasing oxidative injury and increased expression and secretion of the antiinflammatory cytokine TNFα EC: PAR1 mediates vaso-relaxation, however when endothelium is damaged PAR1-mediated response shifts to vaso-constriction 153 .…”