title: miR-134 regulates ischemia/reperfusion injury-induced neuronal cell death by regulating CREB signaling.
abstract: 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.
authors.affiliation: Neurosurgery, Shaanxi Provincial People's Hospital, No. 256 Youyi Western Road, Xi'an, 710068, China, weidonghuangsx@163.com.
authors.forename: Weidong
authors.initials: W
authors.lastname: Huang
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.forename: Facai
authors.initials: F
authors.lastname: Meng
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D015687:Cell Hypoxia; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency*; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; C581995:MIRN134 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger; D005947:Glucose; D010100:Oxygen