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

Abstract

BackgroundIschemic 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.MethodsWestern 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.ResultsThe 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.ConclusionOverall, 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.