miR-134 Regulates Ischemia/Reperfusion Injury-Induced Neuronal Cell Death by Regulating CREB Signaling

摘要

microRNA-134 (miR-134) has been reported to be a brain-specific miRNA and is differently expressed in brain tissues subjected to ischemic injury. However, the underlying mechanism of miR-134 in regulating cerebral ischemic injury remains poorly understood. The current study was designed to delineate the molecular basis of miR-134 in regulating cerebral ischemic injury. Using the oxygen-glucose deprivation (OGD) model of hippocampal neuron ischemia in vitro, we found that the overexpression of miR-134 mediated by recombinant adeno-associated virus (AAV) vector infection significantly promoted neuron death induced by OGD/reoxygenation, whereas the inhibition of miR-134 provided protective effects against OGD/reoxygenation-induced cell death. Moreover, cyclic AMP (cAMP) response element-binding protein (CREB) as a putative target of miR-134 was downregulated and upregulated by miR-134 overexpression or inhibition, respectively. The direct interaction between miR-134 and the 3'-untranslated region (UTR) of CREB mRNA was further confirmed by dual-luciferase reporter assay. Overexpression of miR-134 also inhibited the expression of the downstream gene of CREB, including brain-derived neurotrophic factor (BDNF) and the anti-apoptotic gene Bcl-2, whereas the inhibition of miR-134 upregulated the expression of BDNF and Bcl-2 in neurons after OGD/reoxygenation. Notably, the knockdown of CREB by CREB siRNA apparently abrogated the protective effect of anti-miR-134 on OGD/reoxygenation-induced cell death. Taken together, our study suggests that downregulation of miR-134 alleviates ischemic injury through enhancing CREB expression and downstream genes, providing a promising and potential therapeutic target for cerebral ischemic injury.