MiR-18a Aggravates Intracranial Hemorrhage by Regulating RUNX1-Occludin/ZO-1 Axis to Increase BBB Permeability.

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  • Additional Information
    • Source:
      Publisher: Saunders Country of Publication: United States NLM ID: 9111633 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-8511 (Electronic) Linking ISSN: 10523057 NLM ISO Abbreviation: J Stroke Cerebrovasc Dis Subsets: MEDLINE
    • Publication Information:
      Publication: Philadelphia, PA : Saunders
      Original Publication: New York, NY : Demos Publications, [1991-
    • Subject Terms:
      Capillary Permeability*; Blood-Brain Barrier/*metabolism ; Core Binding Factor Alpha 2 Subunit/*metabolism ; Intracranial Hemorrhages/*metabolism ; MicroRNAs/*metabolism ; Occludin/*metabolism ; Zonula Occludens-1 Protein/*metabolism; Animals ; Astrocytes/metabolism ; Astrocytes/pathology ; Blood-Brain Barrier/pathology ; Cells, Cultured ; Coculture Techniques ; Core Binding Factor Alpha 2 Subunit/genetics ; Disease Models, Animal ; Electric Impedance ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Intracranial Hemorrhages/genetics ; Intracranial Hemorrhages/pathology ; Male ; MicroRNAs/genetics ; Occludin/genetics ; Rats, Sprague-Dawley ; Signal Transduction ; Zonula Occludens-1 Protein/genetics ; Rats
    • Abstract:
      Objectives: To study the molecular mechanisms of miR-18a aggravating intracranial hemorrhage (ICH) by increasing the blood-brain barrier (BBB) permeability.
      Methods: Brain microvascular endothelial cells (BMVECs) and astrocytes were isolated, identified, and co-cultured to establish in vitro BBB model. BMVECs co-cultured with astrocytes were stimulated with or without thrombase and then transfected with miR-18a mimic and/or si-RUNX1. The trans-endothelial electric resistance (TEER) and FlNa flux were measured, respectively. The potential interaction between RUNX1 and miR-18a was also detected. Additionally, SD rats were injected with fresh autologous non-anticoagulant blood into the brain basal ganglia to establish ICH model. After administration with miR-18a, sh-miR-18a, miR-18a+RUNX1, sh-miR-18a+sh-RUNX1, respectively, BBB permeability was assessed.
      Results: After overexpressing miR-18a, the expression levels of RUNX1, Occludin and ZO-1 were decreased, but the Evan's blue contents and brain water contents were significantly increased in ICH rats. Additionally, rat neurological function was impaired, accompanying with an increase of TEER and fluorescein sodium flux. MiR-18a was a direct target of RUNX1 and it could bind to the promoters of RUNX1 to inhibit the expression of Occuldin and ZO-1. Consistently, these phenomena could also be observed in the corresponding cell model. Conversely, miR-18a knockdown or RUNX1 overexpression just presented an improvement effect on ICH.
      Conclusions: MiR-18a plays a critical role during ICH because it targets to RUNX1 to inhibit the expression of tight junction proteins (Occludin and ZO-1) and then disrupt BBB permeability. MiR-18a might be a probable therapeutic target for ICH diseases.
      Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest.
      (Copyright © 2021 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: BBB permeability; ICH; Tight junction protein; miR-18a, RUNX1
    • Accession Number:
      0 (Core Binding Factor Alpha 2 Subunit)
      0 (MIRN18 microRNA, rat)
      0 (MicroRNAs)
      0 (Occludin)
      0 (Ocln protein, rat)
      0 (Runx1 protein, rat)
      0 (Tjp1 protein, rat)
      0 (Zonula Occludens-1 Protein)
    • Publication Date:
      Date Created: 20210602 Date Completed: 20210726 Latest Revision: 20240226
    • Publication Date:
      20240226
    • Accession Number:
      10.1016/j.jstrokecerebrovasdis.2021.105878
    • Accession Number:
      34077824