Calpain调控NF-κB信号通路在病毒感染导致的扩张型心肌病心肌重塑中的作用及机制研究

Coxsackievirus-induced myocardial remodeling is one of the important pathological changes in the progression of viral myocarditis(VMC) to dilated cardiomyopathy(DCM). In the former studies of VMC, we found that the proteinase of calpain was involved in regulating myocardial inflammation and fibrosis, but the mechanisms are still unclear. It has been reported that calpain and NF-κB pathway participated in myocardial remodeling post myocardial infarction and NF-κB pathway altered in VMC. To clarify whether calpain mediated virus-induced myocardial remodeling via NF-κB pathway, this project would utilize the transgenic mouse overexpressing the endogenous calpain inhibitor calpastatin to establish DCM model and observe the effect of virus infection on calpain expression and activity as well as the roles of NF-κB pathway. Furthermore, in-vitro model of virus infection of fibroblast would be studied to observe the role of NF-κB pathway in myocardial remodeling in detail. In summary, the project was dedicated to discuss the mechanisms of calpain in the progression of VMC to DCM via the NF-κB pathway to provide a novel candidate target for the early prevention of such diseases.

柯萨奇病毒持续感染导致的心肌重塑是病毒性心肌炎(VMC)转变成扩张型心肌病(DCM)的重要病理变化之一。我们前期在VMC的研究中发现：体内钙蛋白酶calpain参与调控组织炎症及纤维化，但其详细机制不清楚。已有研究报道，calpain与NF-κB信号通路参与心梗后心肌重塑； 我们以往的研究也发现，NF-κB通路在VMC中有明显的变化。为了弄清calpain是否通过NF-κB通路介导病毒诱导心肌重塑，本研究拟利用过表达calpain内源性抑制剂calpastatin的转基因小鼠建立病毒诱导的DCM模型，观察病毒感染对calpain表达及活性的影响以及NF-κB信号通路的作用；进一步通过体外干预心肌成纤维细胞，明确NF-κB信号通路改变对心肌重塑的影响，从而探讨calpain调控NF-κB信号通路的机制，阐明calpain在VMC向DCM转化中的作用，为早期干预该类疾病的进展提供新的治疗靶点。

病毒感染导致扩张型心肌病的机制尚不清楚。我们研究发现：在病毒性心肌炎中，体内钙蛋白酶calpain参与调控组织炎症及纤维化，提示其可能参与心肌炎心肌重塑过程；既往研究提示calpain与NF-κB信号通路参与心梗后心肌重塑且NF-κB通路参与病毒性心肌炎发病。因此在病毒触发病理性心肌重塑过程中 calpain很可能通过调控NF-κB通路介导病毒性心肌炎向扩张型心肌病转化。本研究就这一问题进行了探讨。利用过表达calpain内源性抑制剂calpastatin的转基因小鼠建立病毒诱导扩张型心肌病模型，观察对病毒感染诱发扩张型心肌病的影响，分析心肌重塑病理过程，检测NF-κB信号通路改变，从而探讨了calpain调控NF-κB信号通路介导心肌重塑导致扩张型心肌病的机制。同时在体外进一步探讨了其具体机制。通过本研究，阐明了calpain在病毒性心肌炎向扩张型心肌病转化中的作用，为扩张型心肌病的治疗提供靶点。