Autophagy alleviates hypoxia-induced blood-brain barrier injury via regulation of CLDN5 (claudin 5)
Autophagy alleviates hypoxia-induced blood-brain barrier injury via regulation of CLDN5 (claudin 5)
复制标题
自噬通过调节 CLDN5 (claudin 5) 减轻缺氧引起的血脑屏障损伤
DOI：
10.1080/15548627.2020.1851897
复制
发表时间：
2020-12
期刊：
影响因子：
13.3
通讯作者：
Jingjing Zhang
中科院分区：
文献类型：
--
作者：
Zhenguo Yang;Panpan Lin;Bing Chen;Xiaoqi Zhang;Wei Xiao;Shuilong Wu;Chunnian Huang;Du Feng;Wenqing Zhang;Jingjing Zhang
摘要血脑屏障（BBB）破坏是脑卒中后中枢神经系统（CNS）继发性损害的关键因素，常与脑微血管内皮细胞（BMEC）的大自噬/自噬异常有关。然而，自噬在维持血脑屏障完整性中的潜在机制仍不清楚。在这里，我们报告说，在中风患者的BMEC中，CLDN5（claudin 5）异常聚集在细胞质中，伴随着自噬激活。在体内斑马鱼和体外细胞研究表明，BBB的破坏部分是由CAV1（小窝蛋白1）介导的重新分配的膜CLDN5进入细胞质在缺氧。同时，自噬被激活，并主要有助于降解BMEC胞质溶胶中的CAV 1和聚集的CLDN5，从而减轻BBB破坏。通过遗传方法或化学物质阻断自噬会加剧CLDN5的胞质聚集，导致更严重的BBB损伤。这些数据表明，自噬通过调节CLDN5再分布来保护BBB完整性，并为BBB障碍相关的脑血管疾病提供了潜在的治疗策略。缩略语：血脑：血脑屏障; BECN 1：1; BMEC：脑微血管内皮细胞; CAV 1：小窝蛋白1; CCA：颈总动脉; CLDN 5：密蛋白5; CNS：中枢神经系统; CQ：氯喹; HIF 1A：缺氧诱导因子1亚基α; MCAO：大脑中动脉闭塞-再灌注; OCLN：闭塞蛋白; ROS：活性氧; STED：受激发射耗竭; TEER：跨内皮电阻; TEM：透射电子显微镜; TJ：紧密连接; TJP 1：紧密连接蛋白1;不间断电源：泛素蛋白酶体系统
ABSTRACT Blood-brain barrier (BBB) disruption is a key event in triggering secondary damage to the central nervous system (CNS) under stroke, and is frequently associated with abnormal macroautophagy/autophagy in brain microvascular endothelial cells (BMECs). However, the underlying mechanism of autophagy in maintaining BBB integrity remains unclear. Here we report that in BMECs of patients suffering stroke, CLDN5 (claudin 5) abnormally aggregates in the cytosol accompanied by autophagy activation. In vivo zebrafish and in vitro cell studies reveal that BBB breakdown is partially caused by CAV1 (caveolin 1)-mediated redistribution of membranous CLDN5 into the cytosol under hypoxia. Meanwhile, autophagy is activated and contributes mainly to the degradation of CAV1 and aggregated CLDN5 in the cytosol of BMECs, therefore alleviating BBB breakdown. Blockage of autophagy by genetic methods or chemicals aggravates cytosolic aggregation of CLDN5, resulting in severer BBB impairment. These data demonstrate that autophagy functions in the protection of BBB integrity by regulating CLDN5 redistribution and provide a potential therapeutic strategy for BBB disorder-related cerebrovascular disease. Abbreviations: BBB: blood-brain barrier; BECN1: beclin 1; BMEC: brain microvascular endothelial cell; CAV1: caveolin 1; CCA: common carotid artery; CLDN5: claudin 5; CNS: central nervous system; CQ: chloroquine; HIF1A: hypoxia inducible factor 1 subunit alpha; MCAO: middle cerebral artery occlusion-reperfusion; OCLN: occludin; ROS: reactive oxygen species; STED: stimulated emission depletion; TEER: trans-endothelial electrical resistance; TEM: transmission electron microscopy; TJ: tight junction; TJP1: tight junction protein 1; UPS: ubiquitin-proteasome system
登录
查看更多内容
DOI：
10.1186/cc7710
发表时间：
2009
期刊：
Critical care (London, England)
影响因子：
--
作者：
Flierl MA;Stahel PF;Rittirsch D;Huber-Lang M;Niederbichler AD;Hoesel LM;Touban BM;Morgan SJ;Smith WR;Ward PA;Ipaktchi K
通讯作者：
Ipaktchi K
DOI：
--
发表时间：
2013
期刊：
--
影响因子：
--
作者：
Woong Y. Hwang;Yanfang Fu;D. Reyon;Morgan L. Maeder;S. Tsai;Jeffry D. Sander;R. Peterson;J.-R. Joanna Yeh-J.
通讯作者：
Woong Y. Hwang;Yanfang Fu;D. Reyon;Morgan L. Maeder;S. Tsai;Jeffry D. Sander;R. Peterson;J.-R. Joanna Yeh-J.
DOI：
--
发表时间：
2011-06
期刊：
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society
影响因子：
--
作者：
E. Ferrero;A. Fulgenzi;D. Belloni;C. Foglieni;M. Ferrero
通讯作者：
E. Ferrero;A. Fulgenzi;D. Belloni;C. Foglieni;M. Ferrero
影响因子：
13.3
作者：
Lee, Eunmyong;Koo, Yeon;Amatruda, James F.
通讯作者：
Amatruda, James F.
WASH 通过抑制 Beclin 1 泛素化来抑制自噬
影响因子：
11.4
作者：
Xia, Pengyan;Wang, Shuo;Fan, Zusen
通讯作者：
Fan, Zusen