Transient inhibition of translation improves long-term cardiac function after ischemia/reperfusion by attenuating the inflammatory response-猫眼课题宝

DOI：

10.1101/2022.07.25.501397

发表时间：

2022-07

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

C. Hofmann;Adrian Serafin;Ole M Schwerdt;Fereshteh Younesi;Florian Sicklinger;I. S. Meyer;Ellen Malovrh;Clara Sandmann;L. Jürgensen;V. Kamuf-Schenk;C. Stroh;Zoe Löwenthal;Mandy Rettel;F. Stein;H. Katus;Tobias Jakobi;N. Frey;F. Leuschner;M. Völkers

快速再灌注是减轻心肌缺血引起的心脏损伤的最有效的治疗方法。然而，再灌注本身通过不完全理解的机制引起心肌损伤，称为缺血/再灌注（I/R）损伤。心肌通过基因表达的变化来适应I/R，这决定了细胞对再灌注的反应。蛋白质翻译是基因表达的关键组成部分。然而，目前尚不清楚翻译的调节如何有助于心脏基因表达对再灌注的反应，以及它是否可以被靶向以减轻I/R损伤。方法为了检测翻译及其对I/R反应中基因表达的影响，我们在体外和体内评估了缺血和再灌注后不同时间点的蛋白质合成。药理学抑制剂被用来剖析翻译控制的潜在分子机制。蛋白质合成的瞬时抑制被用来解释对再灌注的翻译反应对心脏功能和炎症的影响。在I/R小鼠中进行细胞类型特异性核糖体分析，以确定翻译对心肌细胞中基因表达调控的影响。结果再灌注增加心肌细胞在缺血期间从先前抑制状态的翻译速率，这与诱导细胞死亡有关。在体内，I/R导致心肌边缘区翻译的强烈激活。详细的分析显示，翻译的上调是由eIF 4F复合物的形成介导的，这是由mTORC 1 - 4 EBP 1-eIF 4F轴特异性介导的。分别通过4 EGI-1或雷帕霉素对eIF 4F复合物形成的短期药理学抑制，减弱了翻译，减小了梗死面积，并改善了心肌梗死后的长期心脏功能。心肌细胞特异性核糖体分析表明，再灌注损伤增加了与心脏炎症和细胞浸润相关的心肌细胞中mRNA网络的翻译。瞬时抑制mTORC 1 - 4 EBP 1-eIF 4F轴降低了促炎转录物如Ccl 2的表达，从而减少了Ly 6Chi单核细胞浸润和心肌炎症。结论心肌再灌注可诱导边缘区蛋白质合成，通过快速翻译特异性不适应mRNA网络介导免疫细胞浸润和炎症反应，参与I/R损伤。在再灌注期间瞬时抑制mTORC 1 - 4 EBP 1-eIF 4F信号传导轴可减弱这种促炎性翻译反应，防止I/R损伤并改善心肌梗死后的长期心脏功能。临床观点有何新功能？这是第一个研究心肌缺血/再灌注时翻译调控对心肌细胞基因表达的影响的研究。我们发现，翻译调节缺血/再灌注后心肌细胞中约三分之二的差异表达基因，包括许多参与炎症和免疫细胞浸润的基因。对缺血/再灌注的翻译反应由mTORC 1 - 4 EBP 1-eIF 4F轴调节，其通过控制趋化因子Ccl 2的表达来决定促炎性单核细胞浸润。临床意义是什么？目前，没有特异性疗法来预防缺血/再灌注损伤，缺血/再灌注损伤至少部分地由适应不良的炎症反应介导。由mTORC 1 - 4 EBP 1-eIF 4F轴调节的免疫控制网络可以通过短期药物干预来靶向，以减轻小鼠缺血/再灌注后的炎症反应并改善心脏功能。本研究支持选择性抑制炎症反应的适应不良因素以改善心肌梗死后患者结局的新兴概念;此外，它为目前正在进行的CLEVER-ACS试验提供了机制基础。

Rationale Rapid reperfusion is the most effective treatment for attenuating cardiac injury caused by myocardial ischemia. Yet, reperfusion itself elicits damage to the myocardium through incompletely understood mechanisms, known as ischemia/reperfusion (I/R) injury. The myocardium adapts to I/R by changes in gene expression, which determines the cellular response to reperfusion. Protein translation is a key component of gene expression. However, it is unknown how regulation of translation contributes to cardiac gene expression in response to reperfusion and whether it can be targeted to mitigate I/R injury. Methods To examine translation and its impact on gene expression in response to I/R we assessed protein synthesis at different timepoints after ischemia and reperfusion in vitro and in vivo. Pharmacological inhibitors were used to dissect the underlying molecular mechanisms of translational control. Transient inhibition of protein synthesis was undertaken to decipher the effects of the translational response to reperfusion on cardiac function and inflammation. Cell-type-specific ribosome profiling was performed in mice subjected to I/R to determine the impact of translation on the regulation of gene expression in cardiomyocytes. Results Reperfusion increased translation rates from a previously suppressed state during ischemia in cardiomyocytes, which was associated with the induction of cell death. In vivo, I/R resulted in strong activation of translation in the myocardial border zone. Detailed analysis revealed that the upregulation of translation is mediated by eIF4F complex formation, which was specifically mediated by the mTORC1-4EBP1-eIF4F axis. Short-term pharmacological inhibition of eIF4F complex formation by 4EGI-1 or rapamycin, respectively, attenuated translation, reduced infarct size and improved long-term cardiac function after myocardial infarction. Cardiomyocyte-specific ribosome profiling identified that reperfusion damage increased translation of mRNA networks in cardiomyocytes associated with cardiac inflammation and cell infiltration. Transient inhibition of the mTORC1-4EBP1-eIF4F axis decreased the expression of proinflammatory transcripts such as Ccl2, thereby reducing Ly6Chi monocyte infiltration and myocardial inflammation. Conclusions Myocardial reperfusion induces protein synthesis in the border zone which contributes to I/R injury by rapidly translating a specific maladaptive mRNA network that mediates immune cell infiltration and inflammation. Transient inhibition of the mTORC1-4EBP1-eIF4F signaling axis during reperfusion attenuates this proinflammatory translational response, protects against I/R injury and improves long-term cardiac function after myocardial infarction. Clinical Perspective What Is New? This is the first study to investigate the impact of translational regulation on cardiomyocyte gene expression in response to myocardial ischemia/reperfusion. We show that translation regulates approximately two-thirds of differentially expressed genes in cardiomyocytes after ischemia/reperfusion, including many involved in inflammation and immune cell infiltration. The translational response to ischemia/reperfusion is regulated by the mTORC1-4EBP1-eIF4F axis, which determines pro-inflammatory monocyte infiltration via control of the expression of the chemokine Ccl2. What Are the Clinical Implications? Currently, there are no specific therapies to prevent ischemia/reperfusion injury, which is mediated, at least in part, by a maladaptive inflammatory response. A translationally controlled network regulated by the mTORC1-4EBP1-eIF4F axis can be targeted by a short-term pharmacological intervention to attenuate the inflammatory response and improve cardiac function after ischemia/reperfusion in mice. This study supports the emerging concept of selectively inhibiting maladaptive elements of the inflammatory response to improve outcome in patients after myocardial infarction; in addition, it provides a mechanistic basis for the currently ongoing CLEVER-ACS trial.

Transient inhibition of translation improves long-term cardiac function after ischemia/reperfusion by attenuating the inflammatory response

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