Background: Remote ischemic pre-conditioning (RIPC) alleviated the myocardial ischemia-reperfusion injury, yet the underlying mechanisms remain to be fully elucidated, especially at the late phase. Searching a key component as a transfer carrier may provide a novel insight into RIPC-mediated cardioprotection in the condition of myocardial ischemia-reperfusion.

Objective: To investigate the cardioprotective effect of plasma exosomes at the late phase of RIPC and its potential signaling pathways involved.

Methods and Results: Exosomes were isolated from the plasma of rats 48 h after the RIPC or control protocol. Although the total plasma exosomes level had no significant change at the late phase of RIPC (RIPC-exosome) compared with the control exosomes (Control-exosome), the RIPC-exosome afforded remarkable protection against myocardial ischemia-reperfusion (MI/R) injury in rats and hypoxia-reoxygenation (H/R) injury in cells. The miRNA array revealed significant enrichment of miR-126a-3p in RIPC-exosome. Importantly, both miR-126a-3p inhibitor and antagonist significantly blunted the cardioprotection of RIPC-exosome in H/R cells and MI/R rats, respectively, while miR-126a-3p mimic and agomir showed significant cardioprotection against H/R injury in cells and MI/R injury in rats. Mechanistically, RIPC-exosome, especially exosomal miR-126a-3p, activated the reperfusion injury salvage kinase (RISK) pathway by enhancing the phosphorylation of Akt and Erk1/2, and simultaneously inhibited Caspase-3 mediated apoptotic signaling.

Conclusions: Our findings reveal a novel myocardial protective mechanism that plasma exosomes at the late phase of RIPC attenuate myocardial ischemia-reperfusion injury via exosomal miR-126a-3p.

背景：远程缺血预处理（RIPC）减轻了心肌缺血再灌注损伤，但其潜在机制仍有待充分阐明，尤其是在晚期。寻找作为转移载体的关键成分可能为了解 RIPC 介导的心肌缺血再灌注条件下的心脏保护提供新的见解。

客观的： 研究血浆外泌体在 RIPC 晚期的心脏保护作用及其潜在的信号通路。

方法和结果：在 RIPC 或对照方案后 48 小时，从大鼠血浆中分离外泌体。尽管与对照外泌体（Control-exosome）相比，RIPC晚期（RIPC-外泌体）血浆总外泌体水平没有显着变化，但RIPC-外泌体对心肌缺血再灌注（MI/R）损伤提供了显着的保护大鼠和细胞缺氧-复氧 (H/R) 损伤。miRNA 阵列揭示了 RIPC 外泌体中 miR-126a-3p 的显着富集。重要的是，miR-126a-3p 抑制剂和拮抗剂分别显着减弱了 H/R 细胞和 MI/R 大鼠中 RIPC-外泌体的心脏保护作用，而 miR-126a-3p 模拟物和 agomir 对 H/R 损伤显示出显着的心脏保护作用。细胞和大鼠 MI/R 损伤。从机制上讲，RIPC-外泌体，尤其是外泌体 miR-126a-3p，

结论： 我们的研究结果揭示了一种新的心肌保护机制，即 RIPC 晚期的血浆外泌体通过外泌体 miR-126a-3p 减轻心肌缺血再灌注损伤。