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

Liu, Jie; Weaver, John; Jin, Xinchun; Zhang, Yuan; Xu, Jiang; Liu, Ke J.; Li, Weiping; Liu, Wenlan

doi:10.1007/s12035-015-9504-8

Cited by 69 publications

(70 citation statements)

References 45 publications

(74 reference statements)

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“…There are differences between the experimental models used in our study and those used by Li et al While we used 18-h OGD in cells and 24-h MCAO in rats, they used 6-h OGD/4-h reoxygenation in cells and 2-h ischemia/22h reperfusion in rats. Supporting our findings, a recent study by Liu et al demonstrated that another BBB component claudin-5 is degraded by 4-h OGD, but not by 2-h OGD/2-h reoxygenation, and suggested that the degradation of claudin-5 is mediated by caveolin-1 and autophagy-lysosome activation in endothelial cells [38]. However, in vivo experiments were not performed in the study by Liu et al We believe that these previous observations along with our current findings contribute to an integrated understanding of the role of autophagy in ischemic BBB dysfunction.…”

Section: Discussionsupporting

confidence: 91%

“…Our results demonstrated that ischemia-induced autophagy mediated the degradation of occludin and that inhibition of autophagy by 3-MA reversed occludin degradation and attenuated BBB dysfunction. In line with our observation, claudin-5 was degraded by autophagy-lysosome activation in OGD-exposed brain endothelial cells [38], and autophagic activation with BBB damage were observed in p50 knockout mice [39], suggesting that autophagy may contribute to ischemic neuronal and vascular damage. It is also demonstrated that enhanced autophagy during brain ischemia in diabetic mice might be responsible for excessive BBB disruption [40].…”

Section: Discussionsupporting

confidence: 90%

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Autophagy-mediated occludin degradation contributes to blood–brain barrier disruption during ischemia in bEnd.3 brain endothelial cells and rat ischemic stroke models

Kim

et al. 2020

Fluids Barriers CNS

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Background: The blood-brain barrier (BBB) maintains homeostasis of the brain environment by tightly regulating the entry of substances from systemic circulation. A breach in the BBB results in increased permeability to potentially toxic substances and is an important contributor to amplification of ischemic brain damage. The precise molecular pathways that result in impairment of BBB integrity remain to be elucidated. Autophagy is a degradation pathway that clears damaged or unnecessary proteins from cells. However, excessive autophagy can lead to cellular dysfunction and death under pathological conditions. Methods:In this study, we investigated whether autophagy is involved in BBB disruption in ischemia, using in vitro cells and in vivo rat models. We used brain endothelial bEnd.3 cells and oxygen glucose deprivation (OGD) to simulate ischemia in culture, along with a rat ischemic stroke model to evaluate the role of autophagy in BBB disruption during cerebral ischemia.Results: OGD 18 h induced cellular dysfunction, and increased permeability with degradation of occludin and activation of autophagy pathways in brain endothelial cells. Immunostaining revealed that occludin degradation is co-localized with ischemic autophagosomes. OGD-induced occludin degradation and permeability changes were significantly decreased by inhibition of autophagy using 3-methyladenine (3-MA). Enhanced autophagic activity and loss of occludin were also observed in brain capillaries isolated from rats with middle cerebral artery occlusion (MCAO). Intravenous administration of 3-MA inhibited these molecular changes in brain capillaries, and recovered the increased permeability as determined using Evans blue. Conclusions:Our findings provide evidence that autophagy plays an important role in ischemia-induced occludin degradation and loss of BBB integrity.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Autophagy-mediated occludin degradation contributes to blood–brain barrier disruption during ischemia in bEnd.3 brain endothelial cells and rat ischemic stroke models

Kim

et al. 2020

Fluids Barriers CNS

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“…NO can induce autophagy lysosome-mediated claudin-5 degradation in oxygen-glucose deprivation-treated endothelial cells. 42 However, we found here that NO does not induced autophagy at the time and dose used in our study.…”

Section: Discussioncontrasting

confidence: 60%

iNOS-Derived Nitric Oxide Induces Integrin-Linked Kinase Endocytic Lysosome-Mediated Degradation in the Vascular Endothelium

Reventún

Alique

Cuadrado

et al. 2017

ATVB

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Objective-ILK (integrin-linked kinase) plays a key role in controlling vasomotor tone and is decreased in atherosclerosis.The objective of this study is to test whether nitric oxide (NO) regulates ILK in vascular remodeling. Approach and Results-We found a striking correlation between increased levels of inducible nitric oxide and decreased ILK levels in human atherosclerosis and in a mouse model of vascular remodeling (carotid artery ligation) comparing with iNOS (inducible NO synthase) knockout mice. iNOS induction produced the same result in mouse aortic endothelial cells, and these effects were mimicked by an NO donor in a time-dependent manner. We found that NO decreased ILK protein stability by promoting the dissociation of the complex ILK/Hsp90 (heat shock protein 90)/eNOS (endothelial NO synthase), leading to eNOS uncoupling. NO also destabilized ILK signaling platform and lead to decreased levels of paxillin and α-parvin. ILK phosphorylation of its downstream target GSK3-β (glycogen synthase kinase 3 beta) was decreased by NO. Mechanistically, NO increased ILK ubiquitination mediated by the E3 ubiquitin ligase CHIP (C terminus of HSC70-interacting protein), but ILK ubiquitination was not followed by proteasome degradation. Alternatively, NO drove ILK to degradation through the endocytic-lysosomal pathway. ILK colocalized with the lysosome marker LAMP-1 (lysosomal-associated membrane protein 1) in endothelial cells, and inhibition of lysosome activity with chloroquine reversed the effect of NO. Likewise, ILK colocalized with the early endosome marker EEA1 (early endosome antigen 1). ILK endocytosis proceeded via dynamin because a specific inhibitor of dynamin (Dyngo 4a) was able to reverse ILK endocytosis and its lysosome degradation. Conclusions-Endocytosis

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“…In the present study, the level of claudin-2, a cation specific pore forming TJ protein was found to be reduced in ClC-2 over-expressing cells. Though caveolin-1 is known to interact with claudins [32] [55], further studies are needed to delineate the role of ClC-2 in the modulation of claudin-2 protein level.…”

Section: Discussionmentioning

confidence: 99%

Chloride channel ClC- 2 enhances intestinal epithelial tight junction barrier function via regulation of caveolin-1 and caveolar trafficking of occludin

Nighot

Leung

Thomas

2017

Experimental Cell Research

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Previous studies have demonstrated that the chloride channel ClC-2 plays a critical role in intestinal epithelial tight junction (TJ) barrier function via intracellular trafficking of TJ protein occludin. To study the mechanism of ClC-2-mediated TJ barrier function and intracellular trafficking of occludin, we established ClC-2 over-expressing Caco-2 cell line (Caco-2CLCN2) by full length ClC-2 ORF transfection. ClC-2 over-expression (Caco-2CLCN2) significantly enhanced TJ barrier (increased TER by ≥ 2 times and reduced inulin flux by 50%) compared to control Caco-2pEZ cells. ClC-2 over-expression (Caco-2CLCN2) increased occludin protein level compared to control Caco-2pEZ cells. Surface biotinylation assay revealed reduced steady state endocytosis of occludin in Caco-2CLCN2 cells. Furthermore, ClC-2 over-expression led to reduction in caveolin-1 protein level and diminishment of caveolae assembly. Caveolae disruption increased TJ permeability in control but not ClC-2 over-expressing Caco-2CLCN2 cells. Selective ClC-2 channel blocker GaTx2 caused an increase in caveolin-1 protein level and reduced occludin level. Delivery of cell permeable caveolin-1 scaffolding domain reduced the occludin protein level. Over all, these results suggest that ClC- 2 enhances TJ barrier function in intestinal epithelial cells via regulation of caveolin-1 and caveolae-mediated trafficking of occludin.

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

Cited by 69 publications

References 45 publications

Autophagy-mediated occludin degradation contributes to blood–brain barrier disruption during ischemia in bEnd.3 brain endothelial cells and rat ischemic stroke models

Autophagy-mediated occludin degradation contributes to blood–brain barrier disruption during ischemia in bEnd.3 brain endothelial cells and rat ischemic stroke models

iNOS-Derived Nitric Oxide Induces Integrin-Linked Kinase Endocytic Lysosome-Mediated Degradation in the Vascular Endothelium

Chloride channel ClC- 2 enhances intestinal epithelial tight junction barrier function via regulation of caveolin-1 and caveolar trafficking of occludin

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