MicroRNA-128-3p Protects Mouse Against Cerebral Ischemia Through Reducing p38α Mitogen-Activated Protein Kinase Activity
- 317 Downloads
The p38α, also named Mapk14, is a pro-apoptotic protein, which is reported to be downregulated 2 h after cerebral ischemia. However, little is known what causes the downregulation of p38α protein level. Here, we studied the effect of cerebral ischemia on p38α mRNA expression and p38α protein level in brain of mice. We found that p38α protein level is reduced after middle cerebral artery occlusion. However, at the meantime, p38α mRNA expression has no detectable changes, suggesting that the possible posttranscription is regulated by ischemia. To reveal the mechanism for posttranscription of p38α protein, we tested the effect of miR-128-3p. Using luciferase reporter assay, we found that miR-128-3p could directly target p38α 3’UTR. We further tested the effect of miR-128-3p on the p38α protein level. We found that miR-128-3p strongly decreased the p38α protein level in SH-SY5Y cells after the cells were transfected with miR-128-3p using lentivirus vector containing precursor its RNA sequences. We further found that inhibition of miR-128-3p enhanced the infarct volume of brain in mice. Our study thus confirms that miR-128-3p can downregulate p38α protein level through posttranscription and increase of miR-128-3p level may contribute to neuronal survival in ischemia-induced brain injury.
KeywordsmicroRNA p38α Regulation Cerebral ischemia Neuroprotection
We thank Xiaobing Zhang for helpful suggestions on the manuscript. Support is provided by the Shaanxi Science and Technology Research and Development Program (2012-KCT-16).
GCM and GW performed statistical analysis, data interpretation and manuscript preparation. YLZ contributed to study concept, design and supervision. PYR and FY performed literature research and data extraction. YLZ and GW were responsible for quality control of data and accuracy. All authors wrote the manuscript and approved the final version of the paper.
- Agarwal V, Bell GW, Nam JW, Bartel DP (2015) Predicting effective microRNA target sites in mammalian mRNAs eLife:4. doi: 10.7554/eLife.05005
- Bi XY, Wang TS, Zhang M, Liu QQ, Li WB, Zhang Y (2014) The up-regulation of p-p38 MAPK during the induction of brain ischemic tolerance induced by intermittent hypobaric hypoxia preconditioning in rats. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 30:97–100PubMedGoogle Scholar
- Chang JJ, Stanfill A, Pourmotabbed T (2016) The role of matrix metalloproteinase polymorphisms in ischemic stroke. Int J Mol Sci 17. doi: 10.3390/ijms17081323
- Cheng CY, Tang NY, Kao ST, Hsieh CL (2016) Ferulic acid administered at various time points protects against cerebral infarction by activating p38 MAPK/p90RSK/CREB/Bcl-2 anti-apoptotic signaling in the subacute phase of cerebral ischemia-reperfusion injury in rats. PLoS One 11:e0155748. doi: 10.1371/journal.pone.0155748 CrossRefPubMedPubMedCentralGoogle Scholar
- Evangelisti C et al. (2009) MiR-128 up-regulation inhibits Reelin and DCX expression and reduces neuroblastoma cell motility and invasiveness FASEB journal : official publication of the Federation of American Societies for Exp Biol 23:4276–4287 doi: 10.1096/fj.09-134965
- Liu Z, Li Y, Zhang RL, Cui Y, Chopp M (2011) Bone marrow stromal cells promote skilled motor recovery and enhance contralesional axonal connections after ischemic stroke in adult mice. Stroke; a Journal of Cerebral Circulation 42:740–744. doi: 10.1161/strokeaha.110.607226 CrossRefPubMedCentralGoogle Scholar
- Liu XR et al (2012) Ischemic postconditioning diminishes matrix metalloproteinase 9 expression and attenuates loss of the extracellular matrix proteins in rats following middle cerebral artery occlusion and reperfusion. CNS Neuroscience & Therapeutics 18:855–863. doi: 10.1111/j.1755-5949.2012.00366.x CrossRefGoogle Scholar
- Nito C, Kamada H, Endo H, Narasimhan P, Lee YS, Chan PH (2012) Involvement of mitogen-activated protein kinase pathways in expression of the water channel protein aquaporin-4 after ischemia in rat cortical astrocytes. J Neurotrauma 29:2404–2412. doi: 10.1089/neu.2012.2430 CrossRefPubMedPubMedCentralGoogle Scholar
- Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V (2004) Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 5:R13. doi: 10.1186/gb-2004-5-3-r13 CrossRefPubMedPubMedCentralGoogle Scholar
- Zhang QG, Wang R, Khan M, Mahesh V, Brann DW (2008) Role of Dickkopf-1, an antagonist of the Wnt/β-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation. The Journal of neuroscience : the official journal of the Society for Neuroscience 28:8430–8441. doi: 10.1523/jneurosci.2752-08.2008 CrossRefGoogle Scholar
- Zhang, W et al. (2016) MiRNA-128 regulates the proliferation and neurogenesis of neural precursors by targeting PCM1 in the developing cortex. 5. doi: 10.7554/eLife.11324