Plasma Exosomes at the Late Phase of Remote Ischemic Pre-conditioning Attenuate Myocardial Ischemia-Reperfusion Injury Through Transferring miR-126a-3p

Abstract

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.

Exosomal HSP90 induced by remote ischemic preconditioning alleviates myocardial ischemia/reperfusion injury by inhibiting complement activation and inflammation

“…Giricz et al showed for the first time that exosomes isolated from hearts played a protective role in myocardial I/R injury by the transmission of RIPC signal [ 7 ]. Moreover, Li et al [ 8 ] showed that exosomes released from RIPC plasma were crucial in mediating cardioprotective effects through transferring miR-126a-3p.…”

Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection

“…The initial activation of the autophagosome during the first window of protection alleviates the damage of I/R injury and supports cell function by clearing damaged protein aggregates, by removing damaged ROS-producing mitochondria and through the recycling of macromolecules for use in cell repair [ 88 ]. A study of exosomes from rats has shown that this response may appear as long as 48 h after the RIC stimulus [ 89 ]. Preservation of post-ischemic cardiac function, measured by post-ischemic LV end-diastolic and developed pressure, is similar by acute, delayed and repeated RIC in experimental studies of rats and mice [ 88 , 90 , 91 ].…”

Mechanisms and therapeutic strategies of extracellular vesicles in cardiovascular diseases

“…In addition, RIPC‐induced production of plasma exosomes can reduce apoptosis and myocardial I/R injury by paracrine transfer of miR‐24 155 . Moreover, plasma exosomes in late RIPC can reduce myocardial I/R injury through exosomal miR‐126a‐3p 156 . Furthermore, miR‐342‐3p dysregulation in plasma exosomes during early recovery after AMI may cause impaired cardiac protective potential.…”

“… 155 Moreover, plasma exosomes in late RIPC can reduce myocardial I/R injury through exosomal miR‐126a‐3p. 156 Furthermore, miR‐342‐3p dysregulation in plasma exosomes during early recovery after AMI may cause impaired cardiac protective potential. By targeting SOX6 and transcription factor EB ( TFEB ), miR‐342‐3p can enhance exosome‐mediated repair of cardiac injury by suppressing myocardial apoptosis and autophagy.…”