Abstract
Aberrant expression of microRNAs (miRNAs) has been linked with ischemic brain injury (IBI), but the mechanistic actions behind the associated miRNAs remain to be determined. Of note, miR-129-5p was revealed to be downregulated in the serum of patients with IBI. In silico prediction identified a putative target gene, siah E3 ubiquitin protein ligase 1 (SIAH1), of miR-129-5p. Accordingly, this study plans to clarify the functional relevance of the interplay of miR-129-5p and SIAH1 in IBI. IBI was modeled by exposing human hippocampal neuronal cells to oxygen–glucose deprivation (OGD) in vitro and by occluding the middle cerebral artery (MCAO) in a mouse model in vivo. Apoptosis of hippocampal neuronal cells was assessed by annexin V-FITC/PI staining and TUNEL staining. The area of cerebral infarction was measured using TTC staining, along with neurological scoring on modeled mice. Loss of hippocampal neuronal cells in the peri-infarct area was monitored using Nissl staining. Downregulated miR-129-5p expression was found in OGD-induced hippocampal neuronal cells and MCAO-treated mice. Mechanistically, miR-129-5p was validated to target and inhibit SIAH1 through the application of dual-luciferase reporter assay. Additionally, enforced miR-129-5p inhibited the apoptosis of OGD-induced cells and decreased the cerebral infarct area, neurological scores and apoptosis of hippocampal neuronal cells by downregulating SIAH1 and activating the mTOR signaling pathway. Taken together, the results of this study reveal the important role and underlying mechanism of miR-129-5p in IBI, providing a promising biomarker for preventive and therapeutic strategies.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Chen Z, Yang J, Zhong J, Luo Y, Du W, Hu C, Xia H, Li Y, Zhang J, Li M, Yang Y, Huang H, Peng Z, Tan X, Wang H (2020) MicroRNA-193b-3p alleviates focal cerebral ischemia and reperfusion-induced injury in rats by inhibiting 5-lipoxygenase expression. Exp Neurol 327:113223. https://doi.org/10.1016/j.expneurol.2020.113223
Garrosa J, Paredes I, Marambaud P, Lopez MG, Cano-Abad MG (2020) Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices Cells 9. https://doi.org/10.3390/cells9030664
Harraz MM, Tyagi R, Cortes P, Snyder SH (2016) Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation. Mol Psychiatry 21:313–319. https://doi.org/10.1038/mp.2015.211
Li X, Zheng L, Xia Q, Liu L, Mao M, Zhou H, Zhao Y, Shi J (2019) A novel cell-penetrating peptide protects against neuron apoptosis after cerebral ischemia by inhibiting the nuclear translocation of annexin A1. Cell Death Differ 26:260–275. https://doi.org/10.1038/s41418-018-0116-5
Li XQ, Chen FS, Tan WF, Fang B, Zhang ZL, Ma H (2017) Elevated microRNA-129-5p level ameliorates neuroinflammation and blood-spinal cord barrier damage after ischemia-reperfusion by inhibiting HMGB1 and the TLR3-cytokine pathway. J Neuroinflammation 14:205. https://doi.org/10.1186/s12974-017-0977-4
Li Y, Ding R, Wang F, Guo C, Liu A, Wei L, Yuan S, Chen F, Hou S, Ma Z, Zhang Y, Cudmore RH, Wang X, Shen H (2020) Transient ischemia-reperfusion induces cortical hyperactivity and AMPAR trafficking in the somatosensory cortex. Aging (Albany NY) 12:4299–4321. https://doi.org/10.18632/aging.102881
Ma Q, Hou L, Gao X, Yan K (2020) NKAP promotes renal cell carcinoma growth via AKT/mTOR signalling pathway. Cell Biochem Funct 38:574–581. https://doi.org/10.1002/cbf.3508
Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, second ed. Academic Press, San Diego
Peng T, Jiang Y, Farhan M, Lazarovici P, Chen L, Zheng W (2019) Anti-inflammatory Effects of Traditional Chinese Medicines on Preclinical in vivo Models of Brain Ischemia-Reperfusion-Injury: Prospects for Neuroprotective Drug Discovery and Therapy. Front Pharmacol 10:204. https://doi.org/10.3389/fphar.2019.00204
Rossi V, Lispi M, Longobardi S, Mattei M, Di Rella F, Salustri A, De Felici M, Klinger FG (2019) Correction: LH prevents cisplatin-induced apoptosis in oocytes and preserves female fertility in mouse. Cell Death Differ 26:779. https://doi.org/10.1038/s41418-018-0174-8
Saugstad JA (2010) MicroRNAs as effectors of brain function with roles in ischemia and injury, neuroprotection, and neurodegeneration. J Cereb Blood Flow Metab 30:1564–1576. https://doi.org/10.1038/jcbfm.2010.101
Sciarretta S, Zhai P, Shao D, Maejima Y, Robbins J, Volpe M, Condorelli G, Sadoshima J (2012) Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation 125:1134–1146. https://doi.org/10.1161/CIRCULATIONAHA.111.078212
Shang J, Liu N, Tanaka N, Abe K (2012) Expressions of hypoxic stress sensor proteins after transient cerebral ischemia in mice. J Neurosci Res 90:648–655. https://doi.org/10.1002/jnr.22776
Tian X, Gong L, Jin A, Wang Y, Zhou X, Tan Y (2019) E3 ubiquitin ligase siah1 nuclear accumulation is critical for homocysteineinduced impairment of C6 astroglioma cells. Mol Med Rep 20:2227–2235. https://doi.org/10.3892/mmr.2019.10449
Wu C, Zhang X, Chen P, Ruan X, Liu W, Li Y, Sun C, Hou L, Yin B, Qiang B, Shu P, Peng X (2019) MicroRNA-129 modulates neuronal migration by targeting Fmr1 in the developing mouse cortex. Cell Death Dis 10:287. https://doi.org/10.1038/s41419-019-1517-1
Wu L, Xiong X, Wu X, Ye Y, Jian Z, Zhi Z, Gu L (2020) Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury. Front Mol Neurosci 13:28. https://doi.org/10.3389/fnmol.2020.00028
Xing G, Luo Z, Zhong C, Pan X, Xu X (2016) Influence of miR-155 on Cell Apoptosis in Rats with Ischemic Stroke: Role of the Ras Homolog Enriched in Brain (Rheb)/mTOR Pathway. Med Sci Monit 22:5141–5153. https://doi.org/10.12659/msm.898980
Zeng Z, Liu Y, Zheng W, Liu L, Yin H, Zhang S, Bai H, Hua L, Wang S, Wang Z, Li X, Xiao J, Yuan Q, Wang Y (2019) MicroRNA-129-5p alleviates nerve injury and inflammatory response of Alzheimer’s disease via downregulating SOX6. Cell Cycle 18:3095–3110. https://doi.org/10.1080/15384101.2019.1669388
Zhai D, Chin K, Wang M, Liu F (2014) Disruption of the nuclear p53-GAPDH complex protects against ischemia-induced neuronal damage. Mol Brain 7:20. https://doi.org/10.1186/1756-6606-7-20
Zhang C, Zang Y, Hu L, Song Q, Zhao W, Zhang C, Liu H, Gu F (2020) Study on the risk prediction for cerebral infarction after transient ischemic attack: A STROBE compliant study. Medicine (baltimore) 99:e19460. https://doi.org/10.1097/MD.0000000000019460
Zhang H, Zhang X, Zhang J (2018) MiR-129-5p inhibits autophagy and apoptosis of H9c2 cells induced by hydrogen peroxide via the PI3K/AKT/mTOR signaling pathway by targeting ATG14. Biochem Biophys Res Commun 506:272–277. https://doi.org/10.1016/j.bbrc.2018.10.085
Zhao H, Wang J, Gao L, Wang R, Liu X, Gao Z, Tao Z, Xu C, Song J, Ji X, Luo Y (2013) MiRNA-424 protects against permanent focal cerebral ischemia injury in mice involving suppressing microglia activation. Stroke 44:1706–1713. https://doi.org/10.1161/STROKEAHA.111.000504
Zhou XM, Liu J, Wang Y, Zhang SL, Zhao X, Xu X, Pei J, Zhang MH (2018) microRNA-129-5p involved in the neuroprotective effect of dexmedetomidine on hypoxic-ischemic brain injury by targeting COL3A1 through the Wnt/beta-catenin signaling pathway in neonatal rats. J Cell Biochem. https://doi.org/10.1002/jcb.26704
Zhu C, Zhou Q, Luo C, Chen Y (2020) Dexmedetomidine Protects Against Oxygen-Glucose Deprivation-Induced Injury Through Inducing Astrocytes Autophagy via TSC2/mTOR Pathway. Neuromolecular Med 22:210–217. https://doi.org/10.1007/s12017-019-08576-0
Acknowledgements
We acknowledge and appreciate our colleagues for their valuable suggestions and technical assistance for this study.
Author information
Authors and Affiliations
Contributions
Yu Lei conceived and designed the study. Xiaoyuan Jin performed experiments and interpreted the results of experiments. Mingli Sun analyzed the data, prepared figures and drafted the paper. Zhiyong Ji edited and revised the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics statement
All participants signed informed consent forms before enrollment in the study. The Ethics Committee of The First Hospital of Jilin University approved the protocols of our study, which strictly adhered to the principles set forth by the Declaration of Helsinki. Approval of the animal experiments involved in this study was obtained from the Animal Ethics Committee of The First Hospital of Jilin University.
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Lei, Y., Jin, X., Sun, M. et al. miR-129-5p Ameliorates Ischemic Brain Injury by Binding to SIAH1 and Activating the mTOR Signaling Pathway. J Mol Neurosci 71, 1761–1771 (2021). https://doi.org/10.1007/s12031-021-01872-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-021-01872-0