Remote ischaemic preconditioning increases serum extracellular vesicle concentrations with altered micro-RNA signature in CABG patients
Remote ischaemic preconditioning increases serum extracellular vesicle concentrations with altered micro-RNA signature in CABG patients
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DOI：
10.1111/aas.13296
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发表时间：
2019-04-01
影响因子：
2.1
通讯作者：
Peters, Juergen
中科院分区：
文献类型：
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作者：
Frey, Ulrich H.;Klaassen, Marina;Peters, Juergen
背景远程缺血预处理（RIPC）可以减轻心肌缺血/再灌注损伤，但其潜在机制仍然很大程度上未知。最近，含有 microRNA (miRNA) 的细胞外囊泡 (EV) 被证明可以介导可能参与心脏保护的远程细胞间通讯。我们测试了这样的假设：在接受冠状动脉搭桥 (CABG) 手术的麻醉患者中进行 RIPC 会导致 EV 从缺血/再灌注手臂释放到含有心脏保护性 miRNA 的血流中。方法 58 例患者随机接受 RIPC（通过上收缩压袖带充气/放气进行 3 次左臂缺血/再灌注，每次 5/5 分钟）或 Sham 组，子方案包括在异氟醚/舒芬太尼麻醉期间 RIPC/Sham 麻醉前（清醒）以及 RIPC/Sham 后 5 分钟和 60 分钟平行右桡动脉和区域（左锁骨下）静脉采血 可以完成。通过基于聚合物的沉淀方法提取 EV，测量其浓度并分析其 miRNA 特征。结果 RIPC 后五分钟，袖带下游的区域静脉 EV 浓度增加，60 分钟后动脉浓度增加（倍数变化 [fc]：RIPC：1.33 +/- 0.5，Sham：0.91 +/- 0.31；交互作用 P = 0.003）。 RIPC 后 5 分钟，从 EV 中分离出的 26 种 miRNA（阈值 fc：3.0，P < 0.05）的表达有所增加，包括心脏保护性 miR-21。 RIPC 还降低术后肌钙蛋白 I 浓度（AUC RIPC：336 ng/mL x 72 小时 +/- 306 对比假手术：713 +/- 1013；P = 0.041）。结论 远程缺血预处理会增加血清 EV 浓度，很可能是通过患者左臂 (RIPC) 的早期 EV 释放，改变其 miRNA 特征，并与心肌保护相关。因此，EV 浓度增加和 miR 特征改变可能会介导 RIPC 效应。
Background Remote ischaemic preconditioning (RIPC) can attenuate myocardial ischaemia/reperfusion injury but its underlying mechanisms remain largely unknown. Recently, extracellular vesicles (EVs) containing microRNAs (miRNAs) were shown to mediate distant intercellular communication that may be involved in cardioprotection. We tested the hypothesis that RIPC in anaesthetized patients undergoing coronary artery bypass (CABG) surgery results in the release of EVs from the ischaemic/reperfused arm into the blood stream harbouring cardioprotective miRNAs. Methods In 58 patients randomised to RIPC (three 5/5 minutes episodes of left arm ischaemia/reperfusion by suprasystolic blood pressure cuff inflations/deflations) or Sham, a subprotocol comprising of parallel right radial artery and regional (left subclavian) venous blood sampling before (awake) and 5 and 60 minutes after RIPC/Sham during isoflurane/sufentanil anaesthesia could be completed. EVs were extracted by polymer-based precipitation methods, their concentrations measured, and their miRNA signature analysed. Results Five minutes after RIPC, regional venous EV concentrations downstream from the cuff increased and arterial concentrations increased after 60 minutes (fold change [fc]: RIPC: 1.33 +/- 0.5, Sham: 0.91 +/- 0.31; P = 0.003 for interaction). Already 5 minutes after RIPC, expression of 26 miRNAs (threshold fc: 3.0, P < 0.05) isolated from EVs including the cardioprotective miR-21 had increased. RIPC also decreased postoperative Troponin I concentrations (AUC RIPC: 336 ng/mL x 72 hours +/- 306 vs Sham: 713 +/- 1013; P = 0.041). Conclusions Remote ischaemic preconditioning increases serum EV concentrations, most likely by early EV release from the patients' left (RIPC) arm, alters their miRNA signature, and is associated with myocardial protection. Thus, an increased EV concentration with an altered miR-signature may mediate the RIPC effect.