环指蛋白4通过TAK1抑制MAPK信号通路减轻心梗后炎症反应

吉家钗; 符策岗; 陈娟; 邢梦芸; 王康鸣; 张艳姣

doi:10.12125/j.chj.201910013

环指蛋白4通过TAK1抑制MAPK信号通路减轻心梗后炎症反应

Ring Finger Protein 4 alleviates inflammation of heart after myocardial infarction by suppressing MAPK signaling via TAK1

摘要

摘要:
目的探究环指蛋白（ring finger protein，RNF）4在心肌梗死（myocardial infarction，MI）后炎症反应中的作用及其机制
方法心脏特异性过表达RNF4小鼠和C57小鼠进行MI造模，分别记录其死亡率。MI后第28天取材，使用苏木精-伊红染色(Hematoxylin-Eosin Staining，HE)、实时荧光定量PCR（real-time quantitative PCR，qPCR）及Western blot方法检测NRF4过表达对MI后其炎症反应的影响及其机制。采用免疫共沉淀检测NRF4的相互作用蛋白及探究互作蛋白的具体结合域
结果 MI模型中，RNF4蛋白及RNF4 mRNA水平显著下降（P<0.01）；心脏特异性过表达RNF4小鼠与C57小鼠相比，MI后炎症反应较轻，心肌间质淋巴细胞浸入较少，同时死亡率更低。Western blot法检测证实RNF4通过抑制MAPK信号通路减轻MI后炎症反应，随后的Co-IP结果证实，RNF4可以结合和降解转化生长因子β-活化激酶1（transforming growth factor-beta-activated kinase 1，TAK1）；最后通过截短TAK1发现，RNF4与TAK1的第301位氨基酸至第480位氨基酸结构域结合
结论 RNF4通过募集和降解TAK1抑制MAPK信号通路减轻MI后炎症反应，降低MI后死亡率。RNF4可以作为改善MI预后的潜在靶点，具有重大临床意义。

Abstract:
AIM To investigate the roles of Ring Finger Protein 4(RNF4) in inflammation of heart after myocardial infarction (MI) and its potential mechanism
Methods Mice with cardiac-specific over-expression of RNF4 and C57 mice were subjected to myocardial infarction operation and their death rate was recorded respectively. Hearts were harvested at 28 days and then HE staining, qPCR and Western blot were performed to determine the roles of RNF4 over-expression in inflammation after myocardial infarction and its underlying mechanism. Co-immunoprecipitation (Co-IP) was used to explore the potential protein which can interact with RNF4 and its exact interacting domain.
RESULTS In MI model, both protein and mRNA levels of RNF4 decreased in MI mice compared with those in untreated mice (P<0.05). The mice with cardiac-specific over-expression of RNF4 had a lower death rate and a mild inflammatory response characterized by a less infiltration of leukomonocytes in myocardial matrix, compared with C57 mice. The results of Western blot showed that RNF4 mitigated inflammation by suppressing MAPK signaling after MI. Subsequently, the results of Co-IP identified that RNF4 recruited and degraded TAK1. It was found that RNF4 bound the exact domain from 301st amino acid to the 480th amino acid of TAK1.
CONCLUSION RNF4 reduces the inflammatory responses and mortality after myocardial infarction by suppressing MAPK signaling through recruiting and degrading TAK1. RNF4 is a potential target to improve the prognosis of myocardial infarction, which is of great clinical significance.

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