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Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage.

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WOS被引频次:163
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成果类型:
期刊论文
作者:
Liu, Jie;Jin, Xinchun;Liu, Ke J.;Liu, Wenlan
通讯作者:
Liu, WL
作者机构:
[Liu, Wenlan; Liu, Ke J.; Jin, Xinchun; Liu, Jie] Univ New Mexico, Coll Pharm, Hlth Sci Ctr, Albuquerque, NM 87131 USA.
[Liu, Ke J.] Univ New Mexico, Dept Neurol, Hlth Sci Ctr, Albuquerque, NM 87131 USA.
[Liu, Jie] Univ South China, Sch Med, Dept Med Microbiol & Immunol, Hengyang 421001, Hunan, Peoples R China.
通讯机构:
[Liu, WL] Univ New Mexico, Coll Pharm, Hlth Sci Ctr, Albuquerque, NM 87131 USA.
语种:
英文
期刊:
The Journal of neuroscience : the official journal of the Society for Neuroscience
ISSN:
0270-6474
年:
2012
卷:
32
期:
9
页码:
3044-3057
文献类别:
WOS:Article
所属学科:
ESI学科类别:神经系统学&行为学;WOS学科类别:Neurosciences
入藏号:
WOS:000300938100012;PMID:22378877
基金类别:
National Institutes of Health [P20 RR15636, R01 AG031725]; American Heart Association [10BGIA3190010]
机构署名:
本校为第一机构
院系归属:
医学院
摘要:
Blood-brain barrier (BBB) disruption occurs early enough to be within the thrombolytic time window, and this early ischemic BBB damage is closely associated with hemorrhagic transformation and thus emerging as a promising target for reducing the hemorrhagic complications of thrombolytic stroke therapy. However, the mechanisms underlying early ischemic BBB damage remain poorly understood. Here, we investigated the early molecular events of ischemic BBB damage using in vitro oxygen-glucose deprivation (OGD) and in vivo rat middle cerebral artery occlusion (MCAO) models. Exposure of bEND3 monolayer to OGD for 2 h significantly increased its permeability to FITC-labeled dextran and promoted the secretion of metalloproteinase-2 and -9 (MMP-2/9) and cytosolic translocation of caveolin-1 (Cav-1). This same OGD treatment also led to rapid degradation of tight junction protein occludin and dissociation of claudin-5 from the cytoskeleton, which contributed to OGD-induced endothelial barrier disruption. Using selective MMP-2/9 inhibitor SB-3CT (2-[[(4-phenoxyphenyl)sulfonyl]methyl]-thiirane) or their neutralizing antibodies or Cav-1 siRNA, we found that MMP-2 was the major enzyme mediating OGD-induced occludin degradation, while Cav-1 was responsible for claudin-5 redistribution. The interaction between Cav-1 and claudin-5 was further confirmed by coimmunoprecipitation. Consistent with these in vitro findings, we observed fluorescence tracer extravasation, increased gelatinolytic activity, and elevated interstitial MMP-2 levels in ischemic subcortical tissue after 2 h MCAO. Moreover, occludin protein loss and claudin-5 redistribution were detected in ischemic cerebromicrovessels. These data indicate that cerebral ischemia initiates two rapid parallel processes, MMP-2-mediated occludin degradation and Cav-1-mediated claudin-5 redistribution, to cause BBB disruption at early stroke stages relevant to acute thrombolysis.
参考文献:
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Andras IE, 2003, J NEUROSCI RES, V74, P255, DOI 10.1002/jnr.10762
Asahi M, 2001, J NEUROSCI, V21, P7724
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Bang OY, 2007, ANN NEUROL, V62, P170, DOI 10.1002/ana.21174

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