Abstract 997: Innate Immune Adaptor MyD88 Mediates Myocardial Inflammation And Infarction In A Mouse Model Of Ischemia-reperfusion Injury
INTRODUCTION: The innate immune response to ischemia-reperfusion (I/R) is, by far, the most common cause of myocardial inflammation and contributes to ischemic myocardial injury. MyD88 is an adaptor protein critical for transducing signals from most innate immune receptors and plays an important role in host defense against microbial infection; but its role in non-infectious myocardial inflammation and injury following I/R is unclear.
METHODS: I/R injury was studied in wild-type (WT) and MyD88-deficient (MyD88−/−) mice. Mice were anesthetized and mechanically ventilated. The heart was exposed via intercostal thoracotomy. The left coronary artery was ligated for 30 min followed by reperfusion. The coronary artery was re-ligated at 24 hours and fluorescent microsphere was injected into LV to detect area-at-risk (AAR). The hearts were harvested, sectioned, and examined for inflammation or infarct size. Myocardial neutrophil infiltration [GR-1 immunohistochemistry and myeloperoxidase activity] and NF-kB signaling (I-kBa degradation and NF-kB binding activity) were examined to assess myocardial inflammation. In ex vivo studies, isolated mouse hearts were exposed to global ischemia for 20 min followed by reperfusion for 30 min.
RESULTS: In vivo I/R induced significant neutrophil infiltration and NF-kB activation in myocardium in WT mice compared with the sham-operated mice. However, in MyD88−/− mice subjected to the same I/R, the level of neutrophil recruitment and NF-kB signaling was significantly lower compared with WT mice. The ratio of AAR to LV was similar in WT and MyD88−/− mice (34 +/− 3% vs. 41 +/− 3%). However, the ratio of MI to AAR was 58% less in MyD88−/− than in WT mice (14 +/− 2% vs. 33 +/− 6% (p < 0.014, n = 11–12). In a Langendorff model of I/R injury, a system devoid of circulating blood components, global I/R induced similar MI sizes, as a fraction of LV size (MI/LV), in MyD88−/− and WT mice (34 +/− 6% and 25 +/− 7%, respectively, p = 0.3, n = 8).
CONCLUSIONS: These studies demonstrate that systemic MyD88 deficiency decreases myocardial inflammation and infarction after ischemia-reperfusion in vivo and support the hypothesis that MyD88 mediates ischemic myocardial injury via mechanisms that are dependent upon circulating blood components.