Autophagy- and MMP-2/9-mediated Reduction and Redistribution of ZO-1 Contribute to Hyperglycemia-increased Blood-Brain Barrier Permeability During Early Reperfusion in Stroke.

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  • Author(s): Zhang S;Zhang S; An Q; An Q; Wang T; Wang T; Gao S; Gao S; Zhou G; Zhou G
  • Source:
    Neuroscience [Neuroscience] 2018 May 01; Vol. 377, pp. 126-137. Date of Electronic Publication: 2018 Mar 07.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: United States NLM ID: 7605074 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-7544 (Electronic) Linking ISSN: 03064522 NLM ISO Abbreviation: Neuroscience Subsets: MEDLINE
    • Publication Information:
      Publication: [New York?] : Elsevier Science
      Original Publication: Oxford, Elmsford, N. Y., Pergamon Press
    • Subject Terms:
      Autophagy/*physiology ; Hyperglycemia/*metabolism ; Reperfusion Injury/*metabolism ; Stroke/*metabolism ; Zonula Occludens-1 Protein/*metabolism; Animals ; Blood-Brain Barrier/metabolism ; Blood-Brain Barrier/pathology ; Capillary Permeability/physiology ; Caveolin 1/metabolism ; Cells, Cultured ; Disease Models, Animal ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Hyperglycemia/pathology ; Lysosomes/metabolism ; Lysosomes/pathology ; Male ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Microvessels/metabolism ; Microvessels/pathology ; Nitric Oxide/metabolism ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/pathology ; Stroke/pathology
    • Abstract:
      Post-stroke hyperglycemia during early reperfusion increases blood-brain barrier (BBB) permeability and subsequently aggravates brain injury and clinical prognosis. The decreased level of tight junction proteins (TJPs) has been reported but the underlying mechanism remains largely elusive. Herein we designed to investigate the detailed molecular events in brain microvascular endothelial cells (BMECs) ex and in vivo. After oxygen-glucose deprivation (OGD) for 90 min and reperfusion with 8 or 16 mM glucose for 30 min, glucose at 16 mM caused significant decrease in the TJP expression and particularly ZO-1 redistribution from membrane to cytoplasm of BMECs. High glucose also markedly promoted the secretion of MMP-2/9 and oxidative/nitrosative stress, enhanced autophagy and increased the Caveolin-1 and LAMP-2 expression. Moreover, in vivo experiments demonstrated that rapamycin-enhanced autophagy further caused ZO-1 reduction and the increased BBB permeability. Therefore, high-glucose exposure in the early reperfusion causes the BBB disruption, with MMP-2/9-mediated extracellular degradation, caveolin-1-mediated intracellular translocation and autophagy-lysosome-mediated degradation of ZO-1 protein all together involved in the process. The role of MMP-2/-9 and autophagy in the modulation of paracellular permeability was confirmed by pharmacological inhibition. Therefore, our findings may provide new insights into targeting ZO-1 regulation for the purpose of significantly improving the clinical prognosis of ischemic stroke.
      (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)
    • Comments:
      Erratum in: Neuroscience. 2018 Aug 21;386:351. (PMID: 30017532)
    • Contributed Indexing:
      Keywords: ZO-1; autophagy; blood–brain barrier; hyperglycemia; stroke; tight junction proteins
    • Accession Number:
      0 (Cav1 protein, rat)
      0 (Caveolin 1)
      0 (Reactive Oxygen Species)
      0 (Tjp1 protein, rat)
      0 (Zonula Occludens-1 Protein)
      31C4KY9ESH (Nitric Oxide)
      EC 3.4.24.24 (Matrix Metalloproteinase 2)
      EC 3.4.24.24 (Mmp2 protein, rat)
      EC 3.4.24.35 (Matrix Metalloproteinase 9)
      EC 3.4.24.35 (Mmp9 protein, rat)
    • Publication Date:
      Date Created: 20180311 Date Completed: 20190311 Latest Revision: 20190311
    • Publication Date:
      20221213
    • Accession Number:
      10.1016/j.neuroscience.2018.02.035
    • Accession Number:
      29524637