Details

Autor(en) / Beteiligte

• Lu, Dah-Yuu
• Yu, Wei-Hsuan
• Yeh, Wei-Lan
• Tang, Chih-Hsin
• Leung, Yuk-Man
• Wong, Kar-Lok
• Chen, Yuh-Fung
• Lai, Chih-Ho
• Fu, Wen-Mei

Titel

Hypoxia-induced matrix metalloproteinase-13 expression in astrocytes enhances permeability of brain endothelial cells

Ist Teil von

• Journal of cellular physiology, 2009-07, Vol.220 (1), p.163-173

Ort / Verlag

Hoboken: Wiley Subscription Services, Inc., A Wiley Company

Erscheinungsjahr

2009

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• 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.