MicroRNA-488-3p Regulates Neuronal Cell Death in Cerebral Ischemic Stroke Through Vacuolar Protein Sorting 4B (VPS4B)

Li Zhou; Wanxin Yang; Enping Yao; Haiyan Li; Jihui Wang; Kun Wang; Xiaohua Zhong; Zhongxing Peng; Xuming Huang

doi:10.2147/NDT.S255666

MicroRNA-488-3p Regulates Neuronal Cell Death in Cerebral Ischemic Stroke Through Vacuolar Protein Sorting 4B (VPS4B)

Neuropsychiatr Dis Treat. 2021 Jan 7:17:41-55. doi: 10.2147/NDT.S255666. eCollection 2021.

Authors

Li Zhou¹, Wanxin Yang¹, Enping Yao¹, Haiyan Li², Jihui Wang², Kun Wang³, Xiaohua Zhong¹, Zhongxing Peng⁴, Xuming Huang¹

Affiliations

¹ Department of Rehabilitation, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, People's Republic of China.
² Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, People's Republic of China.
³ School of Health Science, Guangdong Pharmaceutical University, Guangzhou 510310, People's Republic of China.
⁴ Department of Neurology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, People's Republic of China.

Abstract

Background: Ischemic stroke, which often occurs with high morbidity, disability, and mortality, is a main cause of brain disease. In various types of human diseases, it is found that microRNAs (miRNAs) are considered as gene regulators. Increasing studies have proved that fluctuation of miRNAs, in the pathologies of ischemic stroke, plays a vital role. However, the accurate regulatory mechanism of cerebral ischemic stroke by miRNAs is still unclear. In this research, we investigated the inhibition mechanism of miR-488-3p on neuronal death through targeting vacuolar protein sorting 4B (VPS4B) in cerebral ischemia/reperfusion (I/R) injury.

Methods: Western blot and qRT-PCR were utilized to detect the miR-488-3p level and VPS4B expression. The cell counting kit-8 (CCK-8) assay was utilized to measure the function of miR-488-3p in cell death induced by oxygen glucose deprivation/reoxygenation (OGD/R). After middle cerebral artery occlusion/reperfusion (MCAO/R), the impact of miR-488-3p on infarct volume in mouse brain was assessed. The targets of miR-488-3p were confirmed by luciferase analysis and bioinformatics software.

Results: The miR-488-3p level remarkably reduced in primary neuronal cells administrated with OGD/R. Similarly, it also decreased in the mouse brain administrated with MCAO/R. Additionally, the up-regulation of miR-488-3p expression suppressed the death of neuronal cells and restrained ischemic brain infarction in ischemia-stroked mice. Besides, the results showed that VPS4B, which could be inhibited by miR-488-3p, was a direct target of miR-488-3p. This research revealed that the inhibition of VPS4B protected the neuronal cells in ischemic stroke both in vitro as well as in vivo. Meanwhile, this inhibition strengthened positive impact generated by miR-488-3p on ischemic injury.

Conclusion: Overall, miR-488-3p played a critical role on neuroprotective function via reducing VPS4B protein level. These results performed a new underlying curative target for the treatment of cerebral ischemic stroke.

Keywords: I/R; VPS4B; ischemia/reperfusion; ischemic stroke; miR-488-3p.

Grants and funding

This work is supported by Guangdong Provincial Natural Science Foundation (NO. 2018A0303130323).