Skip to main content
SpringerLink
Log in

Long Non-coding RNA RMST Worsens Ischemic Stroke via MicroRNA-221-3p/PIK3R1/TGF-β Signaling Pathway

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Much efforts have been made to probe the mechanism underlying ischemic stroke (IS). This study was proposed to uncover the role of long non-coding RNA rhabdomyosarcoma 2 related transcript (RMST) in IS through microRNA-221-3p (miR-221-3p)/phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1)/transforming growth factor-β (TGF-β) axis. Neurological behavioral function, pathological changes in brain tissue, oxidative stress, and inflammation responses in middle cerebral artery occlusion (MCAO) mice were tested. RMST, miR-221-3p, PIK3R1, and TGF-β signaling-related protein expression in brain tissues of MCAO mice were detected. RMST and PIK3R1 were elevated, miR-221-3p was downregulated, and TGF-β pathway was activated in mice after MCAO. Restored miR-221-3p or depleted RMST improved neurological behavioral functions, relieved pathological injury in brain tissue, and repressed oxidative stress and inflammation in mice after MCAO. Depleted PIK3R1 or restored miR-221-3p offsets the negative effects of overexpressed RMST on mice with MCAO. The present work highlights that RMST augments IS through reducing miR-221-3p-mediated regulation of PIK3R1 and activating TGF-β pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data availability

Not applicable.

References

  1. Chen C et al (2020) Electroacupuncture pretreatment prevents ischemic stroke and inhibits Wnt signaling-mediated autophagy through the regulation of GSK-3beta phosphorylation. Brain Res Bull 158:90–98

    Article  CAS  PubMed  Google Scholar 

  2. Li X et al (2020) Anti-neuroinflammatory effect of 3,4-dihydroxybenzaldehyde in ischemic stroke. Int Immunopharmacol 82:106353

    Article  CAS  PubMed  Google Scholar 

  3. Xu T et al (2020) Serum omentin-1 and risk of one-year mortality in patients with ischemic stroke. Clin Chim Acta 505:167–171

    Article  CAS  PubMed  Google Scholar 

  4. Feng H et al (2020) Repurposing antimycotic ciclopirox olamine as a promising anti-ischemic stroke agent. Acta Pharm Sin B 10(3):434–446

    Article  CAS  PubMed  Google Scholar 

  5. Hou XX, Cheng H (2018) Long non-coding RNA RMST silencing protects against middle cerebral artery occlusion (MCAO)-induced ischemic stroke. Biochem Biophys Res Commun 495(4):2602–2608

    Article  CAS  PubMed  Google Scholar 

  6. Cheng H et al (2020) LncRNA RMST-mediated miR-107 transcription promotes OGD-induced neuronal apoptosis via interacting with hnRNPK. Neurochem Int 133:104644

    Article  CAS  PubMed  Google Scholar 

  7. Sun XL et al (2019) LncRNA RMST activates TAK1-mediated NF-kappaB signaling and promotes activation of microglial cells via competitively binding with hnRNPK. IUBMB Life 71(11):1785–1793

    Article  CAS  PubMed  Google Scholar 

  8. Wu J et al (2019) MicroRNA target gene prediction of ischemic stroke by using variational Bayesian inference for Gauss mixture model. Exp Ther Med 17(4):2734–2740

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Peng H et al (2020) MuicroRNA-221 participates in cerebral ischemic stroke by modulating endothelial cell function by regulating the PTEN/PI3K/AKT pathway. Exp Ther Med 19(1):443–450

    CAS  PubMed  Google Scholar 

  10. Zhou XB et al (2020) LncRNAGAS5 sponges miRNA-221 to promote neurons apoptosis by up-regulated PUMA under hypoxia condition. Neurol Res 42(1):8–16

    Article  CAS  PubMed  Google Scholar 

  11. Chang TY et al (2014) miRNome traits analysis on endothelial lineage cells discloses biomarker potential circulating microRNAs which affect progenitor activities. BMC Genomics 15:802

    Article  PubMed  PubMed Central  Google Scholar 

  12. Prasad SS et al (2010) Retinal gene expression after central retinal artery ligation: effects of ischemia and reperfusion. Invest Ophthalmol Vis Sci 51(12):6207–6219

    Article  PubMed  Google Scholar 

  13. Eyileten C et al. (2018) MicroRNAs as diagnostic and prognostic biomarkers in ischemic stroke-a comprehensive review and bioinformatic analysis. Cells 7(12)

  14. Zhang K et al (2019) ALK5 signaling pathway mediates neurogenesis and functional recovery after cerebral ischemia/reperfusion in rats via Gadd45b. Cell Death Dis 10(5):360

    Article  PubMed  PubMed Central  Google Scholar 

  15. Meng H et al (2016) LRG1 promotes angiogenesis through upregulating the TGFbeta1 pathway in ischemic rat brain. Mol Med Rep 14(6):5535–5543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jin J et al (2019) LRG1 promotes apoptosis and autophagy through the TGFbeta-smad1/5 signaling pathway to exacerbate ischemia/reperfusion injury. Neuroscience 413:123–134

    Article  CAS  PubMed  Google Scholar 

  17. Li J et al (2019) miR-219-5p inhibits tau phosphorylation by targeting TTBK1 and GSK-3beta in Alzheimer’s disease. J Cell Biochem 120(6):9936–9946

    Article  CAS  PubMed  Google Scholar 

  18. Xie YL, Zhang B, Jing L (2018) MiR-125b blocks Bax/cytochrome C/caspase-3 apoptotic signaling pathway in rat models of cerebral ischemia-reperfusion injury by targeting p53. Neurol Res 40(10):828–837

    Article  CAS  PubMed  Google Scholar 

  19. Liu XH et al (2019) Early constraint-induced movement therapy affects behavior and neuronal plasticity in ischemia-injured rat brains. Neural Regen Res 14(5):775–782

    Article  PubMed  PubMed Central  Google Scholar 

  20. Doeppner TR et al (2014) Effects of neural progenitor cells on post-stroke neurological impairment-a detailed and comprehensive analysis of behavioral tests. Front Cell Neurosci 8:338

    PubMed  PubMed Central  Google Scholar 

  21. Hua Y et al (2002) Behavioral tests after intracerebral hemorrhage in the rat. Stroke 33(10):2478–2484

    Article  PubMed  Google Scholar 

  22. Wang Y et al (2019) Methylation-dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction. FASEB J 33(12):13145–13160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Qiao P, Yan H, Wang J (2020) EGb761 protects brain microvascular endothelial cells against oxygen-glucose deprivation-induced injury through lncRNA Rmst/miR-150 axis. Neurochem Res 45(10):2398–2408

    Article  CAS  PubMed  Google Scholar 

  24. Jia L et al (2015) Circulating miR-145 is associated with plasma high-sensitivity C-reactive protein in acute ischemic stroke patients. Cell Biochem Funct 33(5):314–319

    Article  CAS  PubMed  Google Scholar 

  25. Tsai PC et al (2013) Serum microRNA-21 and microRNA-221 as potential biomarkers for cerebrovascular disease. J Vasc Res 50(4):346–354

    Article  CAS  PubMed  Google Scholar 

  26. Zhao D et al (2018) miR-221 alleviates the inflammatory response and cell apoptosis of neuronal cell through targeting TNFAIP2 in spinal cord ischemia-reperfusion. NeuroReport 29(8):655–660

    Article  CAS  PubMed  Google Scholar 

  27. Oh SE et al (2018) The Parkinson’s disease gene product DJ-1 modulates miR-221 to promote neuronal survival against oxidative stress. Redox Biol 19:62–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhou Y, Richards AM, Wang P (2019) MicroRNA-221 is cardioprotective and anti-fibrotic in a rat model of myocardial infarction. Mol Ther Nucleic Acids 17:185–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cai W et al (2019) MicroRNA-24 attenuates vascular remodeling in diabetic rats through PI3K/Akt signaling pathway. Nutr Metab Cardiovasc Dis 29(6):621–632

    Article  CAS  PubMed  Google Scholar 

  30. Zhu H et al (2017) TGF-beta1/Smad3 signaling pathway suppresses cell apoptosis in cerebral ischemic stroke rats. Med Sci Monit 23:366–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lou Z et al (2018) Upregulation of NOX2 and NOX4 mediated by TGF-beta signaling pathway exacerbates cerebral ischemia/reperfusion oxidative stress injury. Cell Physiol Biochem 46(5):2103–2113

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the associate editor and the reviewers for their useful feedback that improved this paper.

Funding

This work was supported by the Scientific Research Fund of the Second Affiliated Hospital of Harbin Medical University, subject No. Kybs2015-02 and Funds for postdoctoral research in Heilongjiang Province and Heilongjiang Health and Family Planning Commission Research Project (2017–078).

Author information

Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, Harbin, 150081, China

    Jie Li, Ning Wang, Huan Nie, Shan Wang, Tongtong Jiang, Xuehan Ma, Wenjuan Liu & Kuo Tian

Authors
  1. Jie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ning Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huan Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tongtong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xuehan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenjuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kuo Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Wenjuan Liu and Kuo Tian contributed to study design; Jie Li and Ning Wang contributed to manuscript editing; Huan Nie and Shan Wang contributed to experimental studies; Tongtong Jiang and Xuehan Ma contributed to data analysis.

Corresponding authors

Correspondence to Wenjuan Liu or Kuo Tian.

Ethics declarations

Ethics Approval and Consent to Participate

This experiment was reviewed and approved by the Animal Ethics Association of the Second Affiliated Hospital of Harbin Medical University. Great efforts have been made to relieve pain of animals.

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jie Li and Ning Wang are co-first authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, J., Wang, N., Nie, H. et al. Long Non-coding RNA RMST Worsens Ischemic Stroke via MicroRNA-221-3p/PIK3R1/TGF-β Signaling Pathway. Mol Neurobiol 59, 2808–2821 (2022). https://doi.org/10.1007/s12035-021-02632-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-021-02632-2

Keywords

Search

Navigation