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

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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.

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Abbreviations

miR-134:

MicroRNA-134

OGD:

Oxygen-glucose deprivation

AAV:

Adeno-associated virus

CREB:

Cyclic AMP (cAMP) response element-binding protein

UTR:

Untranslated region

BDNF:

Brain-derived neurotrophic factor

LDH:

Lactate dehydrogenase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

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Conflict of Interests

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Neurosurgery, Shaanxi Provincial People’s Hospital, No. 256 Youyi Western Road, Xi’an, 710068, China

    Weidong Huang, Xiaobin Liu, Jie Cao, Facai Meng, Min Li, Bo Chen & Jie Zhang

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  1. Weidong Huang
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  2. Xiaobin Liu
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  3. Jie Cao
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  4. Facai Meng
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  5. Min Li
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  6. Bo Chen
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  7. Jie Zhang
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Correspondence to Weidong Huang.

Additional information

Weidong Huang and Xiaobin Liu contributed equally to this work.

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Huang, W., Liu, X., Cao, J. et al. miR-134 Regulates Ischemia/Reperfusion Injury-Induced Neuronal Cell Death by Regulating CREB Signaling. J Mol Neurosci 55, 821–829 (2015). https://doi.org/10.1007/s12031-014-0434-0

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