Nitric Oxide Interacts with Caveolin-1 to Facilitate Autophagy-Lysosome-Mediated Claudin-5 Degradation in Oxygen-Glucose Deprivation-Treated Endothelial Cells

被引:54
作者
Liu, Jie [1 ]
Weaver, John [5 ]
Jin, Xinchun [6 ,7 ]
Zhang, Yuan [2 ,3 ,4 ]
Xu, Ji [2 ,3 ,4 ]
Liu, Ke J. [5 ]
Li, Weiping [3 ,4 ]
Liu, Wenlan [2 ,3 ,4 ,5 ]
机构
[1] Tongji Univ, Tongji Hosp, Sch Med, Translat Ctr Stem Cell Res,Stem Cell Res Ctr, Shanghai 200065, Peoples R China
[2] Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Cent Lab, Shenzhen 518035, Peoples R China
[3] Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Dept Neurosurg, Shenzhen 518035, Peoples R China
[4] Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Shenzhen Key Lab Neurosurg, Shenzhen 518035, Peoples R China
[5] Univ New Mexico, Coll Pharm, Dept Pharmaceut Sci, Albuquerque, NM 87131 USA
[6] Soochow Univ, Affiliated Hosp 2, Jiangsu Key Lab Translat Res & Therapy Neuropsych, Suzhou 215004, Peoples R China
[7] Soochow Univ, Affiliated Hosp 2, Inst Neurosci, Suzhou 215004, Peoples R China
基金
中国国家自然科学基金; 美国国家卫生研究院;
关键词
Oxygen-glucose deprivation; Claudin-5; Caveolin-1; Autophagy; Lysosome; BLOOD-BRAIN-BARRIER; MATRIX-METALLOPROTEINASE INHIBITOR; CEREBRAL-ARTERY OCCLUSION; TIGHT JUNCTION STRANDS; OCCLUDIN DEGRADATION; EXPERIMENTAL STROKE; FOCAL ISCHEMIA; DISRUPTION; PROTEINS; SYNTHASE;
D O I
10.1007/s12035-015-9504-8
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Using in vitro oxygen-glucose deprivation (OGD) model, we have previously demonstrated that 2-h OGD induces rapid, caveolin-1-mediated dissociation of claudin-5 from the cellular cytoskeletal framework and quick endothelial barrier disruption. In this study, we further investigated the fate of translocated claudin-5 and the mechanisms by which OGD promotes caveolin-1 translocation. Exposure of bEND3 cells to 4-h OGD, but not 2-h OGD plus 2-h reoxygenation, resulted in claudin-5 degradation. Inhibition of autophagy or the fusion of autophagosome with lysosome, but not proteasome, blocked OGD-induced claudin-5 degradation. Moreover, knockdown of caveolin-1 with siRNA blocked OGD-induced claudin-5 degradation. Western blot analysis showed a transient colocalization of caveolin-1, claudin-5, and LC3B in autolysosome or lipid raft fractions at 2-h OGD. Of note, inhibiting autophagosome and lysosome fusion sustained the colocalization of caveolin-1, claudin-5, and LC3B throughout the 4-h OGD exposure. EPR spin trapping showed increased nitric oxide (NO) generation in 2-h OGD-treated cells, and inhibiting NO with its scavenger C-PTIO or inducible nitric oxide synthase (iNOS) inhibitor 1400W prevented OGD-induced caveolin-1 translocation and claudin-5 degradation. Taken together, our data provide a novel mechanism underlying endothelial barrier disruption under prolonged ischemic conditions, in which NO promotes caveolin-1-mediated delivery of claudin-5 to the autophagosome for autophagy-lysosome-dependent degradation.
引用
收藏
页码:5935 / 5947
页数:13
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