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Active site inhibited factor VIIa attenuates myocardial ischemia/reperfusion injury in mice
Author(s) -
LOUBELE S. T. B. G.,
SPEK C. A.,
LEENDERS P.,
VAN OERLE R.,
ABERSON H. L.,
VAN DER VOORT D.,
HAMULYÁK K.,
PETERSEN L. C.,
SPRONK H. M. H.,
TEN CATE H.
Publication year - 2009
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2008.03232.x
Subject(s) - tissue factor , reperfusion injury , pharmacology , medicine , ischemia , coagulation
Summary. Background: Inhibition of specific coagulation pathways such as the factor VIIa‐tissue factor complex has been shown to attenuate ischemia/reperfusion (I/R) injury, but the cellular mechanisms have not been explored. Objectives: To determine the cellular mechanisms involved in the working mechanism of active site inhibited factor VIIa (ASIS) in the protection against myocardial I/R injury. Methods: We investigated the effects of a specific mouse recombinant in a mouse model of myocardial I/R injury. One hour of ischemia was followed by 2, 6 or 24 h of reperfusion. Mouse ASIS or placebo was administered before and after induction of reperfusion. Results: ASIS administration reduced myocardial I/R injury by more than 40% at three reperfusion times. Multiplex ligation dependent probe amplification (MLPA) analysis showed reduced mRNA expression in the ischemic myocardium of CD14, TLR‐4, interleukin‐1 (IL‐1) receptor‐associated kinase (IRAK) and IκBα upon ASIS administration, indicative of inhibition of toll‐like receptor‐4 (TLR‐4) and subsequent nuclear factor‐κB (NF‐κB) mediated cell signaling. Levels of nuclear activated NF‐κB and proteins influenced by the NF‐κB pathway including tissue factor (TF) and IL‐6 that were increased after I/R, were attenuated upon ASIS administration. After 6 and 24 h of reperfusion, neutrophil infiltration into the area of infarction was decreased upon ASIS administration. There was, however, no evidence of an effect of ASIS on apoptosis (Tunel staining and MLPA analysis). Conclusions: We conclude that the diminished amount of myocardial I/R injury after ASIS administration is primarily due to attenuated inflammation‐related lethal I/R injury, probably mediated through the NF‐κB mechanism.