MicroRNA-144 is a circulating effector of remote ischemic preconditioning
MicroRNA-144 is a circulating effector of remote ischemic preconditioning
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DOI：
10.1007/s00395-014-0423-z
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发表时间：
2014-09-01
影响因子：
9.5
通讯作者：
Redington, Andrew N.
中科院分区：
文献类型：
--
作者：
Li, Jing;Rohailla, Sagar;Redington, Andrew N.
由短暂肢体缺血和再灌注周期引起的远程缺血预处理（rIPC）是一种强大的心脏保护策略，具有额外的多效性。然而，我们对其潜在中介和机制的理解仍然不完整。我们研究了 miR-144 在 rIPC 诱导的心脏保护中的作用。微阵列研究首先证实小鼠心肌中 rIPC 增加，IR 损伤降低 miR-144 水平，rIPC 和静脉注射 miR-144 可以挽救后者。与 miR-144 的全身治疗相结合，可增加 P-Akt、P-GSK3 beta 和 P-p44/42 MAPK，降低 p-mTOR 水平并诱导自噬信号传导，并诱导早期和延迟心脏保护，改善功能恢复并减少梗塞面积，与 rIPC 所实现的效果相似。相反，全身给予特定反义寡核苷酸可降低心肌 miR-144 水平并消除 rIPC 的心脏保护作用。然后我们发现 rIPC 增加了小鼠和人类的血浆 miR-144 水平，但血浆微粒 (50-400 nM) 数量或其 miR-144 含量没有变化。然而，外泌体沉淀中的 miR-144 前体几乎增加了四倍，并且缺乏外泌体的血清中 miR-144 水平显着增加，这反过来又与 miR 携带蛋白 Argonaute-2 水平的增加有关。 microRNA 144 的全身释放在 rIPC 诱导的心脏保护中发挥着关键作用。未来的研究应评估血浆 miR-144 作为肢体缺血诱导的 rIPC 有效性生物标志物的潜力，以及 miR-144 本身是否可能代表一种减少临床缺血再灌注损伤的新疗法。
Remote ischemic preconditioning (rIPC) induced by cycles of transient limb ischemia and reperfusion is a powerful cardioprotective strategy with additional pleiotropic effects. However, our understanding of its underlying mediators and mechanisms remains incomplete. We examined the role of miR-144 in the cardioprotection induced by rIPC. Microarray studies first established that rIPC increases, and IR injury decreases miR-144 levels in mouse myocardium, the latter being rescued by both rIPC and intravenous administration of miR-144. Going along with this systemic treatment with miR-144 increased P-Akt, P-GSK3 beta and P-p44/42 MAPK, decreased p-mTOR level and induced autophagy signaling, and induced early and delayed cardioprotection with improved functional recovery and reduction in infarct size similar to that achieved by rIPC. Conversely, systemic administration of a specific antisense oligonucleotide reduced myocardial levels of miR-144 and abrogated cardioprotection by rIPC. We then showed that rIPC increases plasma miR-144 levels in mice and humans, but there was no change in plasma microparticle (50-400 nM) numbers or their miR-144 content. However, there was an almost fourfold increase in miR-144 precursor in the exosome pellet, and a significant increase in miR-144 levels in exosome-poor serum which, in turn, was associated with increased levels of the miR carriage protein Argonaute-2. Systemic release of microRNA 144 plays a pivotal role in the cardioprotection induced by rIPC. Future studies should assess the potential for plasma miR-144 as a biomarker of the effectiveness of rIPC induced by limb ischemia, and whether miR-144 itself may represent a novel therapy to reduce clinical ischemia-reperfusion injury.