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Background: The inhaled Sevoflurane (Sev) has been implicated to protect myocardial tissues against ischemia/reperfusion (I/R)-evoked injury. Nevertheless, the detailed mechanisms of Sev‐mediated cardioprotection remain basically unknown. This study intends to examine the roles of nuclear enriched abundant transcript 1 (NEAT1), a long non-coding RNA (lncRNA) during the cardioprotection exerted by Sev.Methods: We initially performed I/R surgery in mice, and Sev treatment was given during the perfusion, followed by the determination of cardiac function, myocardial infarction area and myocardial apoptosis for the validation of the model. Then, we conducted lncRNA microarray analysis on Sev-treated hearts to find out lncRNAs with significant differences in expression. The changes of myocardial I/R injury were evaluated by echocardiography, TTC staining and TUNEL assay after establishing mice with NEAT1 upregulation. Afterwards, the targeting miRNA of NEAT1 and the targeting mRNA of the miRNA were screened out through StarBase and microarray analyses to carry out rescue experiments.Results: NEAT1 was downregulated in Sev-treated cardiomyocytes. Overexpression of NEAT1 weakened cardiac function, increased infarct size and increased apoptosis in the presence of Sev. NEAT1 bound to microRNA (miR)-140, which was significantly upregulated in Sev-treated cardiomyocytes. Inhibition of miR-140 expression weakened the cardiac function of Sev-treated mice, increased infarct size and cardiomyocyte apoptosis. miR-140 mediated the RhoA pathway, and the RhoA activity inhibition attenuated miR-140 effects on Sev protection.Conclusion: Sev mitigates myocardial I/R injury by restoring NEAT1 expression and regulating the miR-140/RhoA axis.

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