远端缺血后适应通过外泌体改善心脏骤停后心功能障碍的机制研究

Despite the survival rate from cardiac arrest (CA) is much higher now, in-hospital mortality after resuscitation of CA patients remains greater than 50%. Post-cardiac arrest myocardial dysfunction or post-myocardial arrest dysfunction (PMAD) is an important cause for this and acute ischemia/reperfusion (I/R) is a major cause for PMAD. So searching for effective methods to mitigate PMAD is a significant action to reduce in-hospital mortality for CA patients and also an important scientific problem to be solved. Remote ischemic postconditioning (RPostcon) and exosome have been proven to provide powerful myocardial protection against I/R injury. However, it is not clear whether and how both of them play a role in CA. Our previous study found that RPostcon mitigated PMAD and increased plasma exosome level of rat. Furthermore, plasma exosome from the rat receiving RPostcon after CA significantly reduced hypoxia/reoxygenation (H/R) injury of myocardial cell. Based on this, we aim to explore whether and how RPostcon alleviating PMAD by exosome through in vivo, ex vivo and in vitro study. This project will provide innovative ideas and methods to improve PMAD and increase the rate of survival to discharge of CA patients.

虽然近年复苏成功率逐渐上升，但心脏骤停（CA）患者复苏后的院内死亡率仍高达50%。CA后心功能障碍（PMAD）是复苏后院内高死亡率的关键原因，而急性缺血/再灌注（I/R）损伤是导致PMAD的主要因素。因此，寻找有效的PMAD防治措施是降低CA患者院内死亡率的重要举措，也是当前亟待解决的重大科学问题。研究显示远端缺血后适应（RPostcon）和外泌体（exosome）在I/R损伤中有重要作用，但两者在PMAD中是否有作用及作用机制尚未阐明。本课题组前期研究发现RPostcon可改善大鼠PMAD、升高血浆exosome水平，exosome可减轻心肌细胞缺氧/复氧损伤。本课题拟深入前期研究，从在体、离体、细胞三个层面探讨RPostcon是否通过exosome改善PMAD及其机制，研究成果必将为PMAD防治提供新思路、新方法，从而提高CA患者的出院存活率！

心脏骤停后心肌功能障碍（PCAMD）发生在约三分之二的复苏后患者中，是短期死亡率的关键原因。在针对PCAMD的治疗中，远端缺血适应（RIC）已成为最有前途的策略之一。但PCAMD的治疗具有时间敏感性，每一分钟对于心肌存活都至关重要。在CPR期间进行四个周期的RIC，会给急诊医师带来沉重的负担，并且很难在临床环境中实施。最新的研究证据表明RIC可以改变循环小细胞外囊泡（sEV）的含量。然而，关于sEV是否介导了RIC对PCAMD的保护作用尚不清楚。本研究通过构建大鼠心脏骤停/复苏（CA/CPR）模型，首次证实sEV介导了RIC对CA/CPR的心脏保护作用。随后通过miRNA芯片分析，我们发现sEV中的miR-542-5p含量在RIC后上调，并通过靶向下游效应分子IGF2R，减少心肌细胞凋亡。本研究加深了我们对PCAMD机制的理解，并为复苏后心肌保护提供了新的干预策略。