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-α, 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.

中文翻译：

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心肌细胞中细胞因子 mRNA 的降解可抑制压力超负荷心脏的无菌性炎症。


背景促炎细胞因子在心力衰竭的发病机制中发挥重要作用。负责维持衰竭心脏内无菌炎症的机制仍然不明确。尽管转录控制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反应的动力学。 Regnase-1 是一种 RNase，参与免疫细胞中一组促炎细胞因子 mRNA 的降解。 Regnase-1 在心肌细胞等非免疫细胞中的作用仍有待阐明。方法 为了检查心肌细胞中 Regnase-1 降解促炎细胞因子的作用，制备了心肌细胞特异性 Regnase-1 缺陷型小鼠。通过横向主动脉缩窄的方式使小鼠承受压力超负荷以诱发心力衰竭。术后4周通过超声心动图以及组织学和分子分析评估心脏重塑。通过免疫染色检查炎症细胞浸润。 Interleukin-6 信号传导可通过施用其受体抗体来抑制。 Regnase-1 在心脏中的过度表达是通过腺相关病毒载体介导的基因转移进行的。结果 心肌细胞特异性 Regnase-1 缺陷小鼠在基线条件下没有表现出心脏表型，但与对照同窝小鼠相比，在压力超负荷 4 周后表现出严重炎症和扩张型心肌病。主动脉横缩后 4 周，在 Regnase-1 缺陷的心脏中，Il6 mRNA 水平上调，但其他细胞因子 mRNA（包括肿瘤坏死因子-α）没有上调。 尽管Regnase-1缺陷型心脏和对照心脏中Il6 mRNA水平在术后1周均有所增加，但在术后4周对照心脏中没有显示增加。给予抗白细胞介素 6 受体抗体可减轻心肌细胞特异性 Regnase-1 缺陷小鼠的炎症和心肌病的发展。在严重压力超载的野生型小鼠心脏中，尽管 Regnase-1 的蛋白水平增加，但仍观察到 Il6 mRNA 的持续诱导。腺相关病毒 9 介导的 Regnase-1 心肌细胞靶向基因递送或抗白细胞介素 6 受体抗体的施用可减轻野生型小鼠中由严重压力超负荷引起的心肌病的发展。结论 心肌细胞中 Regnase-1 对细胞因子 mRNA 的降解在抑制衰竭心脏的无菌炎症中发挥着重要作用，Regnase-1 介导的途径可能成为治疗心力衰竭患者的治疗靶点。