Circulation:Regnase-1通过介导细胞因子mRNA降解抑制衰竭心脏的无菌性炎症

2020-03-02 不详 MedSci原创

促炎细胞因子在心力衰竭的发病机制中起着重要作用。衰竭心脏内维持无菌性炎症的机制仍不明确。虽然转录调控对促炎细胞因子基因表达很重要,但mRNA的稳定性也有助于免疫反应的动态。Regnase-1是一种RNase,参与免疫细胞中一系列促炎细胞因子mRNA的降解。但Regnase-1在非免疫细胞(如心肌细胞)中的作用仍有待阐明。为了研究Regnase-1在心肌细胞中介导促炎细胞因子降解的作用,研究人员建立

促炎细胞因子在心力衰竭的发病机制中起着重要作用。衰竭心脏内维持无菌性炎症的机制仍不明确。虽然转录调控对促炎细胞因子基因表达很重要,但mRNA的稳定性也有助于免疫反应的动态。Regnase-1是一种RNase,参与免疫细胞中一系列促炎细胞因子mRNA的降解。但Regnase-1在非免疫细胞(如心肌细胞)中的作用仍有待阐明。

为了研究Regnase-1在心肌细胞中介导促炎细胞因子降解的作用,研究人员建立了心肌细胞特异性Regnase-1缺陷小鼠。采用腹主动脉横缩法诱发小鼠心力衰竭。术后4周通过超声心动图及组织学和分子分析评估心室重构。采用免疫染色检测炎性细胞浸润情况,用IL-6受体抗体抑制IL-6信号。

在起始条件下,心肌特异性Regnase-1缺陷型小鼠没有心脏表型,但在腹主动脉横缩术后4周时,与对照小鼠相比,出现了严重的炎症和扩张性心肌病。术后4周时,Regnase-1缺陷型小鼠的Il-6 mRNA水平上调,其他包括肿瘤坏死因子α在内的其他细胞因子无明显改变。虽然术后一周时,在Regnase-1缺陷型小鼠和对照小鼠心脏Il-6 mRNA水平均增加,但术后4周时对照小鼠的Il-6 mRNA水平恢复正常。予以抗Il6受体抗体可减缓Regnase-1缺陷型小鼠的炎症和心肌扩张进展。在压力严重超负荷的野生型小鼠心脏中,虽然Regnase-1蛋白水平升高,但仍可观察到Il-6 mRNA的持续诱导。外源性过表达Regnase-1或予以抗Il-6受体抗体均可减缓野生型小鼠压力超负荷所诱导的心肌病发展。

在心肌细胞中,Regnase-1所介导的细胞因子mRNA降解在抑制衰竭心脏的无菌性炎症中发挥重要作用,Regnase-1介导的通路或可作为治疗心力衰竭患者的靶点。

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