Myocardial dysfunction is a prime cause of death in sepsis. This study is to delve into the function of lncRNA KCNQ1OT1 in myocardial injury induced by sepsis. Sepsis-induced myocardial injury model in rat was initiated by intraperitoneally injecting of LPS (10 mg/kg) in vivo, and cardiomyocyte H9c2 was treated with LPS to mimic sepsis in vitro. KCNQ1OT1 and miR-192-5p expressions were detected by qRT-PCR. The cell viability was probed with CCK-8 experiment and the apoptosis of the cardiomyocytes was tested using flow cytometry analysis. Western blot was operated to determine apoptosis-related proteins expressions. ELISA was used to evaluate the levels of TNF-α, IL-6, and IL-1β. Bioinformatics analysis, RT-PCR, dual luciferase reporter assay, and RNA immunoprecipitation experiment were utilized to detect the interrelation of genes. Herein, we proved that KCNQ1OT1 was considerably down-regulated, whereas miR-192-5p was markedly increased in myocardial tissues of septic rats. KCNQ1OT1 interrelated with miR-192-5p, and negatively modulated its expression levels. Overexpression of KCNQ1OT1 or the transfection of miR-192-5p inhibitors greatly facilitated the viability and impeded the apoptosis of H9c2 cardiomyocytes. miR-192-5p paired with the 3ʹUTR of XIAP, and repressed its protein expression, and XIAP was modulated positively by KCNQ1OT1. In conclusion, our work indicates that down-regulation of KCNQ1OT1 advances cardiac injury through regulating miR-192-5p/XIAP axis during sepsis.

Impact statement

Sepsis-induced cardiomyopathy remains to be a major challenge to health care systems around the globe. There are no known therapies currently available that can cure the disease. This study provides convincing evidence that KCNQ1OT1 could attenuate sepsis-mediated myocardial injury. We further demonstrate that the beneficial function of KCNQ1OT1 was achieved by regulating the miR-192-5p/XIAP axis. We therefore found a new mechanism of cardioprotective effect of KCNQ1OT1, one which also offers a novel theoretical basis for the therapy of sepsis-induced cardiomyopathy.

中文翻译：

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LncRNA KCNQ1OT1通过调节miR-192-5p / XIAP轴减轻败血症诱导的心肌损伤。

心肌功能障碍是败血症死亡的主要原因。本研究旨在探讨lncRNA KCNQ1OT1在败血症诱发的心肌损伤中的作用。通过体内腹膜内注射LPS（10 mg / kg）建立脓毒症诱发的大鼠心肌损伤模型，并用LPS处理心肌细胞H9c2以模拟体外脓毒症。通过qRT-PCR检测KCNQ1OT1和miR-192-5p表达。用CCK-8实验探测细胞活力，并用流式细胞仪分析心肌细胞的凋亡。进行蛋白质印迹分析以确定凋亡相关蛋白的表达。ELISA用于评估TNF-α，IL-6和IL-1β的水平。利用生物信息学分析，RT-PCR，双重荧光素酶报告基因测定和RNA免疫沉淀实验来检测基因的相互关系。在本文中，我们证明了KCNQ1OT1在脓毒症大鼠的心肌组织中明显下调，而miR-192-5p明显升高。KCNQ1OT1与miR-192-5p相关，并且对其表达水平产生负面影响。KCNQ1OT1的过度表达或miR-192-5p抑制剂的转染大大促进了H9c2心肌细胞的生存能力并阻止了其凋亡。miR-192-5p与XIAP的3ʹUTR配对，并抑制其蛋白质表达，而XIAP被KCNQ1OT1阳性调节。总之，我们的工作表明，KCNQ1OT1的下调通过调节败血症期间的miR-192-5p / XIAP轴来加剧心脏损伤。

影响陈述

败血症引起的心肌病仍然是全球卫生保健系统的主要挑战。目前尚无可治愈该病的已知疗法。这项研究提供了令人信服的证据，表明KCNQ1OT1可以减轻败血症介导的心肌损伤。我们进一步证明，通过调节miR-192-5p / XIAP轴可以实现KCNQ1OT1的有益功能。因此，我们发现了KCNQ1OT1的一种新的心脏保护作用机制，该机制也为脓毒症诱发的心肌病的治疗提供了新的理论基础。