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

我们利用心肌炎、心肌肥厚和心肌梗死的小鼠模型，研究了细胞因子在心脏损伤发病机制中的作用。这些数据表明，无论心脏损伤的原因是什么，炎性细胞因子在心力衰竭的发生和发展中发挥着重要作用。应激激活的MAPK是调节细胞因子表达的重要信号级联信号之一。最重要的是，p38MAPK被认为在病毒感染、压力超负荷和氧化应激反应中诱导心肌肥大和细胞凋亡。本项目旨在通过转基因模型阐明p38MAPK级联蛋白在体内的作用。首先，我们尝试在小鼠中过表达pMAPK。然而，它是胚胎致死的。接下来，我们培育了一株MKK6EE转基因小鼠。MKK6EE是一种调节pMAPK的MKK6的结构活性形式，但在转基因品系中仅在mRNA水平检测到MKK6EE。未检测到MKK6EE蛋白和活性。我们进一步试图造成压力超负荷和心肌梗死，但心肌肥厚或心脏损伤的程度没有区别。因此，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.