Cytokine mRNA Degradation in Cardiomyocytes Restrains Sterile Inflammation in Pressure-Overloaded Hearts
Cytokine mRNA Degradation in Cardiomyocytes Restrains Sterile Inflammation in Pressure-Overloaded Hearts
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DOI：
10.1161/circulationaha.119.044582
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发表时间：
2020-02-25
期刊：
影响因子：
37.8
通讯作者：
Otsu, Kinya
中科院分区：
文献类型：
--
作者：
Omiya, Shigemiki;Omori, Yosuke;Otsu, Kinya
背景：促炎细胞因子在心力衰竭的发病机制中起重要作用。在衰竭的心脏中维持无菌炎症的机制仍然不清楚。虽然转录调控对于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应答的动力学。Regnase-1是一种参与免疫细胞中一组促炎细胞因子mRNA降解的RNA酶。Regnase-1在非免疫细胞，如心肌cardiomyocytes.Methods中的作用仍有待阐明：为了研究Regnase-1在心肌细胞中的促炎细胞因子降解的作用，产生了心肌细胞特异性Regnase-1缺陷小鼠。通过横向主动脉缩窄使小鼠经受压力超负荷以诱导心力衰竭。术后4周通过超声心动图以及组织学和分子生物学分析评估心脏重构。免疫组化染色检测炎性细胞浸润。白细胞介素-6信号传导通过施用其受体抗体来抑制。Regnase-1在心脏中的过表达进行腺相关病毒载体介导的基因transfer.Results：心肌细胞特异性Regnase-1缺陷小鼠在基线条件下没有心脏表型，但表现出严重的炎症和扩张型心肌病后4周的压力超负荷与对照组同窝。在主动脉缩窄后四周，IL 6 mRNA水平上调，但在Regnase-1缺陷的心脏中，其他细胞因子mRNA，包括肿瘤坏死因子-α，没有上调。尽管在Regnase-1缺陷和对照心脏中，IL 6 mRNA水平在手术后1周增加，但在手术后4周对照心脏中没有显示出增加。在心肌细胞特异性Regnase-1缺陷小鼠中，给予抗白细胞介素-6受体抗体可减轻炎症和心肌病的发展。在严重压力超负荷的野生型小鼠心脏中，观察到Il 6 mRNA的持续诱导，即使Regnase-1的蛋白水平增加。腺相关病毒9介导的Regnase-1的心肌细胞靶向基因递送或抗白细胞介素6受体抗体的管理衰减严重压力超负荷诱导的心肌病在wild-type mice.Conclusions的发展：Regnase-1在心肌细胞中的细胞因子mRNA的降解在抑制衰竭心脏的无菌性炎症中起着重要作用，Regnase-1介导的通路可能是治疗心力衰竭患者的治疗靶点。
Background:Proinflammatory cytokines play an important role in the pathogenesis of heart failure. The mechanisms responsible for maintaining sterile inflammation within failing hearts remain poorly defined. Although transcriptional control is important for proinflammatory cytokine gene expression, the stability of mRNA also contributes to the kinetics of immune responses. Regnase-1 is an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs in immune cells. The role of Regnase-1 in nonimmune cells such as cardiomyocytes remains to be elucidated.Methods:To examine the role of proinflammatory cytokine degradation by Regnase-1 in cardiomyocytes, cardiomyocyte-specific Regnase-1-deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction to induce heart failure. Cardiac remodeling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Inflammatory cell infiltration was examined by immunostaining. Interleukin-6 signaling was inhibited by administration with its receptor antibody. Overexpression of Regnase-1 in the heart was performed by adeno-associated viral vector-mediated gene transfer.Results:Cardiomyocyte-specific Regnase-1-deficient mice showed no cardiac phenotypes under baseline conditions, but exhibited severe inflammation and dilated cardiomyopathy after 4 weeks of pressure overload compared with control littermates. Four weeks after transverse aortic constriction, the Il6 mRNA level was upregulated, but not other cytokine mRNAs, including tumor necrosis factor-alpha, in Regnase-1-deficient hearts. Although the Il6 mRNA level increased 1 week after operation in both Regnase-1-deficient and control hearts, it showed no increase in control hearts 4 weeks after operation. Administration of anti-interleukin-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in cardiomyocyte-specific Regnase-1-deficient mice. In severe pressure overloaded wild-type mouse hearts, sustained induction of Il6 mRNA was observed, even though the protein level of Regnase-1 increased. Adeno-associated virus 9-mediated cardiomyocyte-targeted gene delivery of Regnase-1 or administration of anti-interleukin-6 receptor antibody attenuated the development of cardiomyopathy induced by severe pressure overload in wild-type mice.Conclusions:The degradation of cytokine mRNA by Regnase-1 in cardiomyocytes plays an important role in restraining sterile inflammation in failing hearts and the Regnase-1-mediated pathway might be a therapeutic target to treat patients with heart failure.