TAK-242, an antagonist for toll-like receptor 4, protects against myocardial ischemia/reperfusion injury in C57BL/6 mice

Objective To investigate the effect of TAK-242, an antagonist for Toll-like receptor 4, against myocardial ischemia/reperfusion injury (I/R) in C57BL/6 mice along with the underlying mechanism. Methods C57BL/6 Mice (n=36)were randomized into three groups: sham group, I (30 min)/R 24 h model group and I/R+TAK-242 (3 mg/kg) treatment group. At 24 h after reperfusion, cardiac function and myocardial infarct size were evaluated with echocardiography and triphenyltetrazolium chloride (TTC), myocardial pathological pattern in mice was detected by HE staining, the mRNA and protein levels of TLR4 were determined by real time PCR and Western blot respectively, and the serum levels of IL- 6, TNF- α, IL- 10 and HMGB1 were detected by ELISA. Results Our results showed that left ventricular systolic diameters (LVID) were shortened (P<0.01), left ventricular ejection fraction (LVEF) and left ventricular short axis shortening fraction (LVFS) were both decreased significantly (P<0.01)in following I/R mice. Myocardial infarction size was large and myocardial inflammatory cell infiltration was severe in I/R mice. The mRNA and protein levels of TLR4 were elevated(P<0.01), the serum levels of IL-6, TNF-α, IL-10 and HMGB1 in I/R mice were significantly increased compared with the sham group (P<0.01). We found that TAK-242 significantly extended LVID (P<0.05), increased LVEF and LVFS (P<0.05), reduced myocardial infarction and improved myocardial inflammatory cell infiltration, inhibited the mRNA and protein levels of TLR4 (P<0.05), down-regulated the expression of IL-6 and TNF-α (P<0.01), and up-regulated IL-10 and HMGB1 compared with I/R group (P<0. 01). Conclusion Treatment with TAK-242 can significantly reduce myocardial ischemia/reperfusion injury partly via regulating inflammation.