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

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.

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Sevoflurane Alleviates Myocardial Ischemia Reperfusion Injury by Inhibiting P2X7-NLRP3 Mediated Pyroptosis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.768594 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jiaxuan Wu ◽

Wenfeng Cai ◽

Ruiming Du ◽

Haiyang Li ◽

Bin Wang ◽

...

Keyword(s):

Creatine Kinase ◽

Myocardial Ischemia ◽

Protective Effect ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Caspase 1 ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion ◽

In Cells

Myocardial ischemia is common in aging population. This study investigates the protective effect of Sevoflurane on myocardial ischemia reperfusion injury (MIRI) and its underlying mechanism. A total of 87 patients with a history of myocardial ischemia who underwent abdominal surgery with Sevoflurane general anesthesia were recruited in the study. The clinical data, blood pressure, heart rate, pressure-rate quotient (PRQ) and rate-pressure product (RPP) were recorded. Serum samples were collected and heart-type fatty acid binding protein (H-FABP), ischemia modified albumin (IMA), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were measured to observe whether Sevoflurane anesthesia had protective effect on myocardium. In addition, MIRI rats and hypoxia/reoxygenation (H/R) injury cell model was established using neonatal rat ventricular myocytes (NRVM). Rats or NRVM were pretreated with sevoflurane for 45min before hypoxia. The mRNA expression of purinergic receptor-7 (P2X7) and NLR family pyrin domain containing 3(NLRP3) were examined. The protein expression of P2X7, NLRP3, apoptosis-associated speck-like protein (ASC), cysteine aspartic acid specific protease-1(Caspase-1), Gasdermin-D (GSDMD), Bcl-2 Associated X Protein (Bax), B-cell lymphoma-2 (Bcl-2) in myocardial tissue and cells were evaluated. The serum contents of IL-1β, IL-18, Malondialdehyde (MDA), Superoxide dismutase (SOD), Lactate dehydrogenase (LDH), Creatine kinase (CK), and Creatine kinase isoenzymes (CK-MB) were measured. The cellular localization and fluorescence intensity of NLRP3 and ASC in cells were detected. It was found that the secretion of IL-1β and IL-18 decreased in the patients. After I45 min/R3h in SD rats and H3h/R1h in NRVM, the protein expressions of P2X7, NLRP3, ASC, Caspase-1 and GSDMD were increased, the release of IL-1β, IL-18, CK, CK-MB, LDH and MDA were increased, and SOD activity was decreased. Sevoflurane treatment inhibited the high expression of P2X7, NLRP3, ASC, Caspase-1 and GSDMD, inhibited the release of LDH, CK,CK-MB and MDA in cells, and improved the activity of SOD, indicating that Sevoflurane alleviated the damage of MIRI of rats and H/R of NRVM, and had myocardial protective effect. Taken together, our study suggests that Sevoflurane inhibited the expression of IL-1β, IL-18 and GSDMD by inhibiting the P2X7-NLRP3 signaling pathway. It reduced the H/R injury of cardiomyocytes and protected the cardiac function by regulating inflammatory reaction and pyroptosis.

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