Active site inhibited factor VIIa attenuates myocardial ischemia/reperfusion injury in mice

S. T. B. G. Loubele, C. A. Spek, P. Leenders, R. van Oerle, H. L. Aberson, D. van der Voort, K. Hamulyák, L. C. Petersen, H. M. H. Spronk, H. ten Cate

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Abstract

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 hrs 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 3 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 IkappaBalpha upon ASIS administration, indicative of inhibition of toll-like receptor-4 (TLR-4) and subsequent nuclear factor-kappaB (NF-kappaB) mediated cell signaling. Levels of nuclear activated NF-kappaB and proteins influenced by the NF-kappaB pathway including tissue factor (TF) and IL-6 that were increased after I/R, were attenuated upon ASIS administration. After 6 and 24 hrs 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-kB mechanism
Original languageEnglish
Pages (from-to)290-298
JournalJournal of thrombosis and haemostasis
Volume7
Issue number2
DOIs
Publication statusPublished - 2009

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