Objectives: We previously reported that the functional mutation of toll-like receptor 4 (TLR4) in C3H/HeJ mice subjected to myocardial ischemia-reperfusion (MI/R) injury resulted in an attenuation of myocardial infarction size, decrease in activation of JNK, translocation of NF-κB, and reduction in mRNA expression of inflammatory cytokines (TNF-α, IL-1β and MCP-1). In the present study, we evaluated the effect of E5564 (Eisai Inc., Teaneck, NJ), an antagonist for TLR4, on MI/R injury with the goal of defining better therapeutic options for MI/R injury.
Methods: C57BL/6 mice received E5564 (5 mg/kg) intravenously 10 minutes prior to 30 minutes of transient occlusion of LAD, followed by 120 minutes of reperfusion. JNK activation was determined by Western blotting with monoclonal antibodies for the phosphorylated form of JNK. NF-κB activity was measured by detecting translocation of NF-κB to the nucleus. The expression of inflammatory cytokines was measured by ribonuclease protection assay.
Results: Pretreatment of mice with E5564 before MI/R resulted in a reduction in JNK phosphorylation (P=.02030), less nuclear of NF-κB translocation (P=.00007), and a decrease in the expression of inflammatory cytokines (P<.05) in the heart, and the development of a significantly smaller infarct (P=.00112), when compared to hearts from mice treated with vehicle alone. Activation of p38 MAPK or ERK, also observed during MI/R, were not inhibited by E5564.
Conclusion: We conclude that inhibition for TLR4 with E5564 attenuates JNK activation during regional MI/R injury and substantially reduces infarct size (by 45.4%). Thus, TLR4 inhibition may have a role in the treatment of MI/R.

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