Analysis of the role of p38 MAP kinase in heart failure using transgenic mice

我们利用小鼠心肌炎、心肌肥厚和心肌梗死模型，探讨细胞因子在心肌损伤发生中的作用。这些数据表明，无论心脏损伤的原因如何，炎症细胞因子在心力衰竭的发生和进展中起着重要作用。应激激活的MAPKs是调控细胞因子表达的重要信号级联之一。综上所述，p38MAPK被认为在病毒感染、压力过载和氧化应激的反应中诱导心脏肥大和凋亡。本项目旨在通过转基因模型阐明p38MAPK级联在体内的作用。首先，我们尝试在小鼠中过表达pMAPK。然而，它是胚胎致命的。接下来，我们培育了一株MKK6EE转基因小鼠。MKK6EE是调控pMAPK的MAPKK中MKK6的组成活性片段。然而，在转基因系中，MKK6EE仅在mRNA水平上检测到。未检测到MKK6EE蛋白和活性。我们进一步尝试制造压力过载和心肌梗死，但心肌肥厚的程度和心肌损伤的程度并无差异。由此提示，MKK6-p38信号通路参与了胚胎的早期发育。

We investigated the role of cytokines in the pathogenesis of cardiac injury using murine model of myocarditis, cardiac hypertrophy, and myocardial infarction. These data suggest that inflammatory cytokines play an important role in the development and progression of heart failure regardless of the cause of cardiac injury. Stress-activated MAPKs are one of the important signal cascade which regulate the expression of cytokines. Above all, p38MAPK is suggested to induce cardiac hypertrophy and apoptosis in responses to viral infection, pressure overload, and oxidative stress. This project is designed to clarify the in vivo role of p38MAPK cascade by transgenic model. First we tried to overexpress pMAPK in mouse. However it was embryonic lethal. Next, we developed a line of MKK6EE transgenic mouse. MKK6EE is a constitutively active from of MKK6, a MAPKK which regulates pMAPK.In the transgenic line, however, MKK6EE was detected only at mRNA level. No MKK6EE protein nor activity was detected. We further tried to make pressure-overload and myocardial infarction in that mice, but the extent of cardiac hypertrophy or the cardiac injury was not different. Thus, it was suggested that MKK6-p38 signaling is involved in the early development of embryo.