Abstract P3071: Ikkε Deficiency Reduces P38 Activity Of Macrophages To Increases Cardiac Injury

Abstract

Background: Inhibitor of NF-κB kinase ε (IKKε) is a non-classical modulator of nuclear factor-kappa B (NF-κB), and is reported to regulate inflammation in various diseases. In this study, the involvement of IKKε in pathophysiological responses was examined in a mouse myocardial infarction model. Methods: MI was induced in IKKε-/- mice by coronary artery ligation. Neutrophils and macrophages were isolated from the heart tissues or bone marrows for further comparison studies by Western blot, PCR, and flow cytometry. Cell phenotypes were identified by immunofluorescence staining. Results: The IKKε-/- group showed poor early survival rate, high circulating IL-6 level, large cardiac fibrosis, and low ejection fraction (30.33±5.25% vs. 34.02±5.53%, p<0.05) compared with the wild type group. Further study revealed that the numbers of neutrophils and macrophages in the heart were higher in the IKKε-/- group than in the PBS group. Macrophage phenotype was more inflammatory along with lower p38 activity in the IKKε-/- group. Importantly, we identified macrophage-myofibroblast transition (MMT) in the infarcted myocardium and found that the number of MMT F4/80(+)SMA(+) cells was 2-fold higher in the IKKε-/- group. The inactivation of p38 accelerated MMT in human macrophages, and the level of phosphorylated p38 was lower in infarct zone of human failing heart tissues. Conclusion: Collectively, IKKε-p38 axis may lead macrophages to aggravated inflammation and accelerated MMT, resulting in poor outcome after myocardial infarction. Here, we suggest that restoring IKKε or p38 in macrophages could be the target to attenuate cardiac inflammation.