MicroRNA-181a–2–3p shuttled by mesenchymal stem cell-secreted extracellular vesicles inhibits oxidative stress in Parkinson’s disease by inhibiting EGR1 and NOX4

Author:

Ma JianjunORCID,Shi Xiaoxue,Li Mingjian,Chen Siyuan,Gu Qi,Zheng Jinhua,Li Dongsheng,Wu Shaopu,Yang Hongqi,Li Xue

Abstract

AbstractThe current study investigated the physiological mechanisms by which extracellular vesicle (EV)-encapsulated miR-181a–2–3p derived from mesenchymal stem cells (MSCs) might mediate oxidative stress (OS) in Parkinson’s disease (PD). First, 6-hydroxydopamine (6-OHDA)-induced PD cell and mouse models were established, after which miR-181a–2–3p, EGR1, and NOX4 expression patterns were determined in SH-SY5Y cells and substantia nigra (SN) of PD mice. Next, the binding affinity among miR-181a–2–3p, EGR1, and NOX4 was identified using multiple assays. Gain- or loss-of-function experiments were further adopted to detect SH-SY5Y cell proliferation and apoptosis and to measure the levels of SOD, MDA, and ROS. Finally, the effects of miR-181a–2–3p from MSC-derived EVs in PD mouse models were also explored. It was found that miR-181a–2–3p was poorly expressed in 6-OHDA-induced SH-SY5Y cells, whereas miR-181a–2–3p from MSCs could be transferred into SH-SY5Y cells via EVs. In addition, miR-181a–2–3p could target and inhibit EGR1, which promoted the expression of NOX4. The aforementioned miR-181a–2–3p shuttled by MSC-derived EVs facilitated SH-SY5Y proliferation and SOD levels, but suppressed apoptosis and MDA and ROS levels by regulating EGR1 via inhibition of NOX4/p38 MAPK, so as to repress OS of PD. Furthermore, in PD mice, miR-181a–2–3p was carried by EVs from MSCs to alleviate apoptosis of dopamine neurons and OS, accompanied by increased expressions of α-syn and decreased 4-HNE in SN tissues. Collectively, our findings revealed that MSC-derived EV-loaded miR-181a–2–3p downregulated EGR1 to inhibit OS via the NOX4/p38 MAPK axis in PD.

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology

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