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Hypoxia-Induced MicroRNA-212/132 Alter Blood-Brain Barrier Integrity Through Inhibition of Tight Junction-Associated Proteins in Human and Mouse Brain Microvascular Endothelial Cells

Blood-brain barrier (BBB) integrity is one of the important elements of central nervous system (CNS) homeostasis. MicroRNAs (miRs) have been demonstrated to play a role in many CNS disorders such as stroke and traumatic brain injury. MiR-212/132 are highly expressed in the CNS but their role at the...

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Autores principales: Burek, Malgorzata, König, Anna, Lang, Mareike, Fiedler, Jan, Oerter, Sabrina, Roewer, Norbert, Bohnert, Michael, Thal, Serge C., Blecharz-Lang, Kinga G., Woitzik, Johannes, Thum, Thomas, Förster, Carola Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842347/
https://www.ncbi.nlm.nih.gov/pubmed/30617994
http://dx.doi.org/10.1007/s12975-018-0683-2
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author Burek, Malgorzata
König, Anna
Lang, Mareike
Fiedler, Jan
Oerter, Sabrina
Roewer, Norbert
Bohnert, Michael
Thal, Serge C.
Blecharz-Lang, Kinga G.
Woitzik, Johannes
Thum, Thomas
Förster, Carola Y.
author_facet Burek, Malgorzata
König, Anna
Lang, Mareike
Fiedler, Jan
Oerter, Sabrina
Roewer, Norbert
Bohnert, Michael
Thal, Serge C.
Blecharz-Lang, Kinga G.
Woitzik, Johannes
Thum, Thomas
Förster, Carola Y.
author_sort Burek, Malgorzata
collection PubMed
description Blood-brain barrier (BBB) integrity is one of the important elements of central nervous system (CNS) homeostasis. MicroRNAs (miRs) have been demonstrated to play a role in many CNS disorders such as stroke and traumatic brain injury. MiR-212/132 are highly expressed in the CNS but their role at the BBB has not been characterized yet. Thus, we analyzed the expression of miR-212/132 in hypoxic mouse and human brain microvascular endothelial cells (BMEC) as well as in posttraumatic mouse and human brain tissue and serum exosomes. MiR-212/132 expression was detected in brain capillaries by in situ hybridization and was increased up to ten times in hypoxic BMEC. Over-expression of pre-miR-212/132 in BMEC decreased barrier properties and reduced migration of BMEC in the wound healing assay. We identified and validated tight junction proteins claudin-1 (Cldn1), junctional adhesion molecule 3 (Jam3), and tight junction-associated protein 1 (Tjap1) as potential miR-212/132 targets. Over-expression of miRs led to a decrease in mRNA and protein expression of Cldn1, Jam3, and Tjap1, which could be rescued by a respective anti-miR. In conclusion, our study identifies miR-212/132 as critical players at the hypoxic BBB. In addition, we propose three new direct miR-212/132 targets to be involved in miR-212/132-mediated effects on BBB properties. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12975-018-0683-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-68423472019-11-22 Hypoxia-Induced MicroRNA-212/132 Alter Blood-Brain Barrier Integrity Through Inhibition of Tight Junction-Associated Proteins in Human and Mouse Brain Microvascular Endothelial Cells Burek, Malgorzata König, Anna Lang, Mareike Fiedler, Jan Oerter, Sabrina Roewer, Norbert Bohnert, Michael Thal, Serge C. Blecharz-Lang, Kinga G. Woitzik, Johannes Thum, Thomas Förster, Carola Y. Transl Stroke Res Original Article Blood-brain barrier (BBB) integrity is one of the important elements of central nervous system (CNS) homeostasis. MicroRNAs (miRs) have been demonstrated to play a role in many CNS disorders such as stroke and traumatic brain injury. MiR-212/132 are highly expressed in the CNS but their role at the BBB has not been characterized yet. Thus, we analyzed the expression of miR-212/132 in hypoxic mouse and human brain microvascular endothelial cells (BMEC) as well as in posttraumatic mouse and human brain tissue and serum exosomes. MiR-212/132 expression was detected in brain capillaries by in situ hybridization and was increased up to ten times in hypoxic BMEC. Over-expression of pre-miR-212/132 in BMEC decreased barrier properties and reduced migration of BMEC in the wound healing assay. We identified and validated tight junction proteins claudin-1 (Cldn1), junctional adhesion molecule 3 (Jam3), and tight junction-associated protein 1 (Tjap1) as potential miR-212/132 targets. Over-expression of miRs led to a decrease in mRNA and protein expression of Cldn1, Jam3, and Tjap1, which could be rescued by a respective anti-miR. In conclusion, our study identifies miR-212/132 as critical players at the hypoxic BBB. In addition, we propose three new direct miR-212/132 targets to be involved in miR-212/132-mediated effects on BBB properties. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12975-018-0683-2) contains supplementary material, which is available to authorized users. Springer US 2019-01-08 2019 /pmc/articles/PMC6842347/ /pubmed/30617994 http://dx.doi.org/10.1007/s12975-018-0683-2 Text en © The Author(s) 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Burek, Malgorzata
König, Anna
Lang, Mareike
Fiedler, Jan
Oerter, Sabrina
Roewer, Norbert
Bohnert, Michael
Thal, Serge C.
Blecharz-Lang, Kinga G.
Woitzik, Johannes
Thum, Thomas
Förster, Carola Y.
Hypoxia-Induced MicroRNA-212/132 Alter Blood-Brain Barrier Integrity Through Inhibition of Tight Junction-Associated Proteins in Human and Mouse Brain Microvascular Endothelial Cells
title Hypoxia-Induced MicroRNA-212/132 Alter Blood-Brain Barrier Integrity Through Inhibition of Tight Junction-Associated Proteins in Human and Mouse Brain Microvascular Endothelial Cells
title_full Hypoxia-Induced MicroRNA-212/132 Alter Blood-Brain Barrier Integrity Through Inhibition of Tight Junction-Associated Proteins in Human and Mouse Brain Microvascular Endothelial Cells
title_fullStr Hypoxia-Induced MicroRNA-212/132 Alter Blood-Brain Barrier Integrity Through Inhibition of Tight Junction-Associated Proteins in Human and Mouse Brain Microvascular Endothelial Cells
title_full_unstemmed Hypoxia-Induced MicroRNA-212/132 Alter Blood-Brain Barrier Integrity Through Inhibition of Tight Junction-Associated Proteins in Human and Mouse Brain Microvascular Endothelial Cells
title_short Hypoxia-Induced MicroRNA-212/132 Alter Blood-Brain Barrier Integrity Through Inhibition of Tight Junction-Associated Proteins in Human and Mouse Brain Microvascular Endothelial Cells
title_sort hypoxia-induced microrna-212/132 alter blood-brain barrier integrity through inhibition of tight junction-associated proteins in human and mouse brain microvascular endothelial cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842347/
https://www.ncbi.nlm.nih.gov/pubmed/30617994
http://dx.doi.org/10.1007/s12975-018-0683-2
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