miR-455 inhibits neuronal cell death by targeting TRAF3 in cerebral ischemic stroke

Abstract

Ischemic stroke is one of the leading causes of brain disease, with high morbidity, disability, and mortality. MicroRNAs (miRNAs) have been identified as vital gene regulators in various types of human diseases. Accumulating evidence has suggested that aberrant expression of miRNAs play critical roles in the pathologies of ischemic stroke. Yet, the precise mechanism by which miRNAs control cerebral ischemic stroke remains unclear. In the present study, we explored whether miR-455 suppresses neuronal death by targeting TRAF3 in cerebral ischemic stroke. The expression levels of miR-455 and TRAF3 were detected by quantitative real-time polymerase chain reaction and Western blot. The role of miR-455 in cell death caused by oxygen–glucose deprivation (OGD) was assessed using Cell Counting Kit-8 (CCK-8) assay. The influence of miR-455 on infarct volume was evaluated in mouse brain after middle cerebral artery occlusion (MCAO). Bioinformatics softwares and luciferase analysis were used to find and confirm the targets of miR-455. The results showed that the expression levels of miR-455 significantly decreased in primary neuronal cells subjected to OGD and mouse brain subjected to MCAO. In addition, forced expression of miR-455 inhibited neuronal death and weakened ischemic brain infarction in focal ischemia-stroked mice. Furthermore, TRAF3 was proved to be a direct target of miR-455, and miR-455 could negatively suppress TRAF3 expression. Biological function analysis showed that TRAF3 silencing displayed the neuroprotective effect in ischemic stroke and could enhance miR-455-induced positive impact on ischemic injury both in vitro and in vivo. Taken together, miR-455 played a vital role in protecting neuronal cells from death by downregulating TRAF3 protein expression. These findings may represent a novel latent therapeutic target for cerebral ischemic stroke.

Role of TRAF3 in neurological and cardiovascular diseases: an overview of recent studies

“…In stroke, TRAF3 is associated with neuronal death (11,13), although other associations with other neurological conditions such as spinal cord injury (SCI) (15) and multiple sclerosis (17) have also been observed. In cardiovascular disease, an altered expression of TRAF3 is related with cardiac hypertrophy (10), atherosclerosis (18,19) and arterial injury (20).…”

“…The authors observed that the inhibition of TRAF3 expression by miR-455 binding reduced infarct size in mice brains after MCAO and suppressed neuronal death in cortical neuronal culture after oxygen-glucose deprivation (11). After MCAO, levels of miR-455 decreased, increasing TRAF3 expression, which in turn increased neuronal death and, thereby, infarct size (11).…”

“…After MCAO, levels of miR-455 decreased, increasing TRAF3 expression, which in turn increased neuronal death and, thereby, infarct size (11).…”

“…TRAF3 regulates multiple pathways through its interaction with receptors, adaptors, kinases and regulatory proteins (10,11). The main pathways regulated by TRAF3 are the canonical and non-canonical NF-κβ pathway (12) and the JNK pathway (13).…”

MicroRNA-9a-5p Alleviates Ischemia Injury After Focal Cerebral Ischemia of the Rat by Targeting ATG5-Mediated Autophagy

“…However, overexpression of miR-181 by miR-181 agomir induced infarct volume and reduced microglia activation [15]. MicroRNA-455 is involved in inhibiting neuronal death by regulating TRAF3 expression in cerebral ischemic stroke [16], which suggesting that miRNAs may be as mediators under stroke status.…”