Claudin-5 Affects Endothelial Autophagy in Response to Early Hypoxia.
Claudin-5 Affects Endothelial Autophagy in Response to Early Hypoxia.
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Claudin-5 影响早期缺氧反应的内皮细胞自噬
DOI：
10.3389/fphys.2021.737474
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发表时间：
2021
影响因子：
4
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Yu P;Li Y;Zhong G;Li W;Chen B;Zhang J
脑卒中后脑血管内皮细胞（EC）的低血糖损伤导致血脑屏障（BBB）功能障碍，这通常与内皮紧密连接（TJ）的破坏和通透性增加有关。因此，维持BBB的结构完整性和适当功能对于中枢神经系统（CNS）的稳态和生理功能至关重要。我们的前期研究表明，在短期饥饿或缺氧条件下，自噬通过调节TJ蛋白Claudin-5的动态变化来保护BBB。在这里，我们表明，在斑马鱼和体外细胞中，膜Claudin-5的损失反过来决定缺氧诱导的自噬脑血管内皮细胞的发生。内皮细胞Claudin-5的缺失可部分减轻短期缺氧损伤引起的内皮细胞凋亡。机制研究表明，在低氧条件下，膜型Claudin-5的存在影响了低氧诱导因子1 α亚基（HIF-1a）和诱导型一氧化氮合酶（iNOS）的激活，从而导致Claudin-5在胞浆中的转位和胞吞。同时，Claudin-5的缺失影响了BCL 2/腺病毒E1 B 19 kDa蛋白相互作用蛋白3（Bnip 3）的下游表达和活性氧（ROS）的产生。这些共同抑制缺氧条件下的内皮细胞自噬。这一发现为阐明缺氧性血脑屏障损伤机制及其保护机制提供了理论依据。
Hypoxic injury to cerebrovascular endothelial cells (ECs) after stroke leads to blood-brain barrier (BBB) dysfunction, which is commonly associated with disruptions of endothelial tight junctions (TJs) and increased permeability. Therefore, maintaining the structural integrity and proper function of the BBB is essential for the homeostasis and physiological function of the central nervous system (CNS). Our previous study revealed that autophagy functions on protecting the BBB by regulating the dynamics of Claudin-5, the essential TJ protein, under short-term starvation or hypoxia conditions. Here, we show that in zebrafish and in vitro cells, loss of membranous Claudin-5 conversely determine the occurrence of hypoxia-induced autophagy in cerebrovascular ECs. Absence of endothelial Claudin-5 could partly attenuate endothelial cell apoptosis caused by short-term hypoxic injury. Mechanism studies revealed that under hypoxic conditions, the existence of membranous Claudin-5 affects the stimulation of hypoxia inducible factor 1 subunit alpha (HIF-1a) and the inducible nitric oxide synthase (iNOS), which are responsible for the translocation of and endocytosis of caveole-packaged Claudin-5 into cytosol. Meanwhile, loss of Claudin-5 affects the generation of reactive oxygen species (ROS) and the downstream expression of BCL2/adenovirus E1B 19kDa protein interacting protein 3 (Bnip3). These together suppress the endothelial autophagy under hypoxia. This finding provides a theoretical basis for clarifying the mechanism of hypoxia-induced BBB injury and its potential protection mechanisms.
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DOI：
10.1042/cs20190728
发表时间：
2020-11-13
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Steinz MM;Santos-Alves E;Lanner JT
通讯作者：
Lanner JT
DOI：
10.1038/nri2607
发表时间：
2009-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
7.8
作者：
Nitta, T;Hata, M;Tsukita, S
通讯作者：
Tsukita, S
自噬在缺血性中风发病机制中的作用
影响因子：
5.3
作者：
Shi Q;Cheng Q;Chen C
通讯作者：
Chen C
影响因子：
7.3
作者：
Kadry H;Noorani B;Cucullo L
通讯作者：
Cucullo L