The TIR/BB-Loop Mimetic AS-1 Protects the Myocardium From Ischaemia/Reperfusion Injury

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AimsInnate immune and inflammatory responses are involved in myocardial ischaemia/reperfusion (I/R) injury. The interleukin-1 receptor (IL-1R)-mediated, MyD88-dependent nuclear factor kappa B (NF-κB) activation pathway plays an important role in the induction of innate immunity and inflammation. However, the role of the IL-1R-MyD88 pathway in myocardial I/R injury has not been thoroughly investigated. We hypothesized that inhibition of the interaction of IL-1R with MyD88 will attenuate myocardial ischaemic injury through reducing inflammatory responses.Methods and resultsMale C57BL/6 mice were subjected to myocardial ischaemia (45 min) followed by reperfusion (4 h). In the treatment group, after mice were subjected to ischaemia (45 min), the TIR/BB-loop mimetic (AS-1), which inhibits the interaction of IL-1R with MyD88, was administered immediately before reperfusion. Hearts were harvested and cellular proteins were isolated for immunoprecipitation and immunoblotting. AS-1 administration significantly decreased infarct size by 32.92 compared with the untreated I/R group. Ejection fraction and fractional shortening in AS-1-treated mice were also significantly increased by 18.0 and 25.6, respectively, compared with the untreated I/R group. AS-1 administration significantly decreased the I/R-increased interaction between IL-1R and MyD88, attenuated the I/R-increased NF-κB binding activity, and reduced levels of inflammatory cytokines and adhesion molecules in the myocardium compared with the untreated I/R group. In addition, AS-1 administration significantly decreased myocardial myeloperoxidase activity by 23.6 and neutrophil infiltration in the myocardium compared with the untreated I/R group.ConclusionThe results demonstrated an important role for the IL-1R-mediated MyD88-dependent signalling pathway in myocardial I/R injury. The data suggest that modulation of the IL-1R/MyD88 interaction could be a strategy for reducing myocardial ischaemic injury.