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Hypoxia‐induced matrix metalloproteinase‐13 expression in astrocytes enhances permeability of brain endothelial cells
Authors:Dah‐Yuu Lu  Wei‐Hsuan Yu  Wei‐Lan Yeh  Chih‐Hsin Tang  Yuk‐Man Leung  Kar‐Lok Wong  Yuh‐Fung Chen  Chih‐Ho Lai  Wen‐Mei Fu
Affiliation:1. Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, Taiwan;2. Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan;3. Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan;4. Department of Pharmacology, China Medical University, Taichung, Taiwan;5. Department of Physiology, China Medical University, Taichung, Taiwan;6. Department of Anesthesiology, China Medical University and Hospital, Taichung, Taiwan;7. Graduate Institute of Chinese Pharmaceutical Sciences, College of Pharmacy, China Medical University, Taichung, Taiwan;8. Department of Microbiology, College of Medicine, China Medical University, Taichung, Taiwan
Abstract:Matrix metalloproteinase‐13 (MMP‐13) is involved in the degradation of extracellular matrix in many kinds of tissues. Here we found that hypoxia increased MMP‐13 protein and mRNA levels in primary rat astrocyte cultures. Hypoxia stimulation also increased the secretion of MMP‐13 from astrocytes, as shown by zymographic analysis. In addition, exposure to hypoxia up‐regulated the expression of c‐Fos and c‐Jun time‐dependently. Hypoxia‐induced MMP‐13 overexpression was antagonized by transfection with antisense oligodeoxynucleotides (AS‐ODN) of c‐Fos or c‐Jun. Furthermore, hypoxic‐conditioned medium (Hx‐CM) collected from astrocytes exposed to hypoxia increased paracellular permeability of adult rat brain endothelial cells (ARBECs). Administration of MMP‐13 neutralizing antibody antagonized Hx‐CM‐induced paracellular permeability of ARBECs. Furthermore, pre‐transfection of astrocytes with AS‐ODN of c‐Fos, c‐Jun or MMP‐13‐shRNA significantly decreased hyperpermeability of ARBECs induced by Hx‐CM. The arrangement of tight junction protein (TJP) zonular occludens‐1 (ZO‐1) of ARBECs disorganized in response to Hx‐CM. Administration of Hx‐CM to ARBECs also resulted in the production of proteolytic fragments of ZO‐1, which was antagonized by transfection of MMP‐13‐shRNA in primary astrocytes. Administration of MMP‐13 recombinant protein to ARBECs led to the disorganization and fragmentation of ZO‐1 protein and also increased paracellular permeability. These results suggest that hypoxia‐induced MMP‐13 expression in astrocytes is regulated by c‐Fos and c‐Jun. MMP‐13 is an important factor leading to the disorganization of ZO‐1 and hyperpermeablility of blood–brain barrier in response to hypoxia. J. Cell. Physiol. 220: 163–173, 2009. © 2009 Wiley‐Liss, Inc.
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