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hUC-MSC-EV-miR-24 enhances the protective effect of dexmedetomidine preconditioning against myocardial ischemia–reperfusion injury through the KEAP1/Nrf2/HO-1 signaling

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Abstract

The cardioprotective effect of microRNAs (miRNAs) on myocardial ischemic-reperfusion (I/R) injury has been documented. Here, we aim to decipher the mechanism of miR-24 delivered by human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) in myocardial I/R injury after dexmedetomidine (DEX) preconditioning. We collected and identified hUC-MSCs and extracted EVs, which were co-cultured with DEX-preconditioned hypoxia/reoxygenation (H/R) cardiomyocyte models or injected into I/R mouse models. The cardiomyocytes and myocardial injury were evaluated by molecular biology experiments. miR-24 was highly expressed in hUC-MSC-EVs. hUC-MSC-EVs could transfer miR-24 into cardiomyocytes where miR-24 augmented cell viability and inhibited cell apoptosis after DEX preconditioning. In the co-culture system of RAW264.7 macrophages with hUC-MSC-EVs, miR-24 promoted M2-type polarization of macrophages and reduced M1-type macrophage polarization. Mechanistically, miR-24 targeted KEAP1 and inhibited its expression, resulting in disruption of the Nrf2/HO-1 signaling. In vivo data confirmed that miR-24 delivered by hUC-MSC-EVs enhanced the suppressing effect of DEX preconditioning on inflammation and apoptosis in rats following myocardial I/R injury. Overall, miR-24 delivered by hUC-MSC-EVs can promote M2 polarization of macrophages and enhance the protective effect of DEX preconditioning on myocardial I/R injury by down-regulating the KEAP1/Nrf2/HO-1 signaling axis.

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Funding

This work was supported by the Excellent Youth Foundation of Hunan Provincial Department of Education (19B477), Project of Hunan Provincial Health Commission (20200018, 20200037), Natural Science Foundation of Hunan Province (2021JJ70043), and Guiding Project of Hengyang Science and Technology Bureau (202121034637).

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Authors and Affiliations

  1. Department of Anesthesiology, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, 421001, People’s Republic of China

    Zixin Hou, Fengrui Yang, Kemin Chen, Yuxia Wang, Jie Qin & Feng Liang

  2. Department of Anesthesiology, Hengyang Medical School, Affiliated Huaihua Hospital, University of South China, Huaihua, 418000, People’s Republic of China

    Fengrui Yang

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  1. Zixin Hou
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Contributions

ZXH planned the experiments; FRY AND KMC performed the experiments, prepared the Figs. and analyzed the data; YXW performed some of the experiments; JQ was responsible for the collection of the clinical samples; FL contributed to drafting the manuscript All authors have read and approved the final submitted manuscript.

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Correspondence to Feng Liang.

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This study was implemented in the light of the Declaration of Helsinki and the guidelines issued by National Institutes of Health (Bethesda, MA) and ratified by the clinical ethics committee of The First Affiliated Hospital, Hengyang Medical School, University of South China. Human umbilical cords were obtained from infants with parental consent. Animal experiments were implemented in the light of the institutional animal care and use committee of The First Affiliated Hospital, Hengyang Medical School, University of South China.

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Hou, Z., Yang, F., Chen, K. et al. hUC-MSC-EV-miR-24 enhances the protective effect of dexmedetomidine preconditioning against myocardial ischemia–reperfusion injury through the KEAP1/Nrf2/HO-1 signaling. Drug Deliv. and Transl. Res. 14, 143–157 (2024). https://doi.org/10.1007/s13346-023-01388-7

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