Adiponectin controls the apoptosis and the expression of tight junction proteins in brain endothelial cells through AdipoR1 under beta amyloid toxicity

Methylglyoxal (MG) is a dicarbonyl compound, the level of which is increased in the blood of diabetes patients. MG is reported to be involved in the development of cerebrovascular complications in diabetes, but the exact mechanisms need to be elucidated. Here, we investigated the possible roles of oxidative stress and mitophagy in MG-induced functional damage in brain endothelial cells (ECs). Treatment of MG significantly altered metabolic stress as observed by the oxygen-consumption rate and barrier-integrity as found in impaired trans-endothelial electrical resistance in brain ECs. The accumulation of MG adducts and the disturbance of the glyoxalase system, which are major detoxification enzymes of MG, occurred concurrently. Reactive oxygen species (ROS)-triggered oxidative damage was observed with increased mitochondrial ROS production and the suppressed Akt/hypoxia-inducible factor 1 alpha (HIF-1α) pathway. Along with the disturbance of mitochondrial bioenergetic function, parkin-1-mediated mitophagy was increased by MG. Treatment of N-acetyl cysteine significantly reversed mitochondrial damage and mitophagy. Notably, MG induced dysregulation of tight junction proteins including occludin, claudin-5, and zonula occluden-1 in brain ECs. Here, we propose that diabetic metabolite MG-associated oxidative stress may contribute to mitochondrial damage and autophagy in brain ECs, resulting in the dysregulation of tight junction proteins and the impairment of permeability.

Download Full-text

Inhibition of telomerase activity alters tight junction protein expression and induces transendothelial migration of HIV-1-infected cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01126.2009 ◽

2010 ◽

Vol 298 (4) ◽

pp. H1136-H1145 ◽

Cited By ~ 12

Author(s):

Wen Huang ◽

Geun Bae Rha ◽

Lei Chen ◽

Melissa J. Seelbach ◽

Bei Zhang ◽

...

Keyword(s):

Endothelial Cells ◽

Tight Junction ◽

Transendothelial Migration ◽

Telomerase Activity ◽

Brain Endothelial Cells ◽

Tight Junction Proteins ◽

Junction Protein ◽

Infected Cells ◽

Hiv 1 ◽

Junction Proteins

Telomerase, via its catalytic component telomerase reverse transcriptase (TERT), extends telomeres of eukaryotic chromosomes. The importance of this reaction is related to the fact that telomere shortening is a rate-limiting mechanism for human life span that induces cell senescence and contributes to the development of age-related pathologies. The aim of the present study was to evaluate whether the modulation of telomerase activity can influence human immunodeficiency virus type 1 (HIV-1)-mediated dysfunction of human brain endothelial cells (hCMEC/D3 cells) and transendothelial migration of HIV-1-infected cells. Telomerase activity was modulated in hCMEC/D3 cells via small interfering RNA-targeting human TERT (hTERT) or by using a specific pharmacological inhibitor of telomerase, TAG-6. The inhibition of hTERT resulted in the upregulation of HIV-1-induced overexpression of intercellular adhesion molecule-1 via the nuclear factor-κB-regulated mechanism and induced the transendothelial migration of HIV-1-infected monocytic U937 cells. In addition, the blocking of hTERT activity potentiated a HIV-induced downregulation of the expression of tight junction proteins. These results were confirmed in TERT-deficient mice injected with HIV-1-specific protein Tat into the cerebral vasculature. Further studies revealed that the upregulation of matrix metalloproteinase-9 is the underlying mechanisms of disruption of tight junction proteins in hCMEC/D3 cells with inhibited TERT and exposed to HIV-1. These results indicate that the senescence of brain endothelial cells may predispose to the HIV-induced upregulation of inflammatory mediators and the disruption of the barrier function at the level of the brain endothelium.

Download Full-text

Interleukin-34 Restores Blood–Brain Barrier Integrity by Upregulating Tight Junction Proteins in Endothelial Cells

PLoS ONE ◽

10.1371/journal.pone.0115981 ◽

2014 ◽

Vol 9 (12) ◽

pp. e115981 ◽

Cited By ~ 20

Author(s):

Shijie Jin ◽

Yoshifumi Sonobe ◽

Jun Kawanokuchi ◽

Hiroshi Horiuchi ◽

Yi Cheng ◽

...

Keyword(s):

Endothelial Cells ◽

Tight Junction ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Tight Junction Proteins ◽

Barrier Integrity ◽

Blood Brain ◽

Blood Brain Barrier Integrity ◽

Junction Proteins

Download Full-text

Decursin Inhibits VEGF-Mediated Inner Blood—Retinal Barrier Breakdown by Suppression of VEGFR-2 Activation

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.78 ◽

2009 ◽

Vol 29 (9) ◽

pp. 1559-1567 ◽

Cited By ~ 22

Author(s):

Jin Hyoung Kim ◽

Jeong Hun Kim ◽

You Mie Lee ◽

Eun-Mi Ahn ◽

Kyu-Won Kim ◽

...

Keyword(s):

Endothelial Cells ◽

Tight Junction ◽

Vision Loss ◽

Retinal Vessels ◽

Tight Junction Proteins ◽

Blood Retinal Barrier ◽

Retinal Endothelial Cells ◽

Extracellular Signal ◽

Brb Breakdown ◽

Junction Proteins

The blood—retinal barrier (BRB) is essential for the normal structural and functional integrity of the retina, whose breakdown could cause the serious vision loss. Vascular endothelial growth factor (VEGF), as a permeable factor, induces alteration of tight junction proteins to result in BRB breakdown. Herein, we demonstrated that decursin inhibits VEGF-mediated inner BRB breakdown through suppression of VEGFR-2 signaling pathway. In retinal endothelial cells, decursin inhibited VEGF-mediated hyperpermeability. Decursin prevented VEGF-mediated loss of tight junction proteins including zonula occludens-1 (ZO-1), ZO-2, and occludin in retinal endothelial cells, which was also supported by restoration of tight junction proteins in intercellular junction. In addition, decursin significantly inhibited VEGF-mediated vascular leakage from retinal vessels, which was accompanied by prevention of loss of tight junction proteins in retinal vessels. Decursin significantly suppressed VEGF-induced VEGFR-2 phosphrylation that consequently led to inhibition of extracellular signal-regulated kinase (ERK) 1/2 activation. Moreover, decursin induced no cytotoxicity to retinal endothelial cells and no retinal toxicity under therapeutic concentrations. Therefore, our results suggest that decursin prevents VEGF-mediated BRB breakdown through blocking of loss of tight junction proteins, which might be regulated by suppression of VEGFR-2 activation. As a novel inhibitor to BRB breakdown, decursin could be applied to variable retinopathies with BRB breakdown.

Download Full-text

Correlation of tight junction morphology with the expression of tight junction proteins in blood-brain barrier endothelial cells

European Journal of Cell Biology ◽

10.1078/0171-9335-00101 ◽

2000 ◽

Vol 79 (10) ◽

pp. 707-717 ◽

Cited By ~ 132

Author(s):

Stefan Liebner ◽

Uwe Kniesel ◽

Hubert Kalbacher ◽

Hartwig Wolburg

Keyword(s):

Endothelial Cells ◽

Tight Junction ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Tight Junction Proteins ◽

Blood Brain ◽

Junction Proteins

Download Full-text

Abstract 3754: Homocysteine Induces Alternations Of Tight Junction Proteins In Brain Endothelial Cells.

Stroke ◽

10.1161/str.43.suppl_1.a3754 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Neetu Tyagi ◽

Natia Qipshidze ◽

Srikanth Givvimani ◽

Paras K Mishra ◽

David Lominadze ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Tight Junction ◽

Kinase Inhibitors ◽

Mitogen Activated Protein Kinase ◽

High Dose ◽

Tight Junction Proteins ◽

Filamentous Actin ◽

Mek Kinase ◽

Junction Proteins

Hyperhomocysteinmia (HHcy) is associated with neurological disorders (Stroke, Alzheimer, Parkinson etc) and causes blood brain barrier (BBB) dysfunction. We previously showed that an elevated level of homocysteine (Hcy) increased formation of filamentous actin and enhanced endothelial layer permeability. In the present work we tested the hypothesis that Hcy induces oxidative stress and binding to endothelial cells (ECs) alters expression of endothelial tight junction proteins (TJP). In this study mouse brain microvascular endothelial cells (bEND3) were grown in gold plated chambers of an electrical cell-substrate impedance system, 8-well chambered. Confluent bEND3 were treated with different doses of Hcy with mitogen-activated protein kinase (MEK) kinase inhibitors (PD98059 or U0126) or H 2 O 2 (oxidant), or medium alone for 24 h. Reactive oxygen species (ROS) was detected using DCFH-DA assay. Hcy induced a dose-dependent decrease in EC junction integrity as determined by transendothelial electrical resistance (TEER). Our results show that high dose of Hcy induces oxidative stress, which cause down regulation of the TJPs contents occludin, zona occluden-1 (ZO-1), and zona occluden-2 (ZO-2) in bEND3s. Hcy-induced decreases in contents of the TJPs were blocked by PD98059, U0126. While BQ788 inhibited endothelin-1-induced decrease in TEER, it did not affect Hcy-induced decrease in TEER. These data suggest that Hcy increases EC layer permeability via the MEK kinase signaling pathway by affecting TJPs, which are bound to actin filaments. Therefore, increased binding of Hcy with ECs during cerebo-vascular diseases may increase microvascular permeability by altering the content and possibly subcellular localization of endothelial TJPs.

Download Full-text

MMP-2 and MMP-9 Secreted by Leukemic Cells Increase the Permeability of Blood-Brain Barrier by Disrupting Tight Junction Proteins In Central Nervous System Leukemia

Blood ◽

10.1182/blood.v116.21.2694.2694 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2694-2694

Author(s):

Sa-ran Feng ◽

Zi-Xing Chen ◽

Jian-nong Cen ◽

Hong-jie Shen ◽

Li Yao ◽

...

Keyword(s):

Central Nervous System ◽

Endothelial Cells ◽

Nervous System ◽

Acute Leukemia ◽

Tight Junction ◽

Blood Brain Barrier ◽

Leukemia Cell ◽

Leukemic Cells ◽

Tight Junction Proteins ◽

Junction Proteins

Abstract Abstract 2694 Recurrence of acute leukemia (AL) in the central nervous system (CNS) confers a poor prognosis. However, little is known about the the underlying mechanisms of leukemic cell infiltration into the CNS. The blood brain barrier (BBB) makes CNS become a refugee to leukemic cells and serves as a resource of cells that seed extraneural sites. Tight junction in brain microvessel endothelial cells (HMECs) constituted by tight junction proteins is an important structure of BBB. Except the well known role of degrading extracellular matrix in metastasis of cancer cells, here we identify matrix metalloproteinase 2 (MMP-2) and MMP-9 secreted by leukemic cells are also associated with BBB opening by degrading tight junction proteins. We have successfully established an animal model of CNS leukemia by using a highly invasive human acute monocytic leukemia cell line SHI-1 in nude mice. Multiple organs including skull and brain were sectioned and determined histopathologically for leukemia cell infiltration. The fact that the down- regulation of ZO-1, Claun-5 and Occludin accompanied with up-regulation of MMP-2 and MMP-9 was correlated with BBB breakdown in mice with CNS leukemia was found when examined by laser scanning fluorescence confocal microscopy and gelatin in situ zymography. The treatment with MMP-inhibitor GM6001 could significantly reverse these changes in tight junction proteins. In an in vitro monolayer BBB model made by human encephalo-microvessel endothelial cells and matreil gel, MMP-2 and MMP-9 specifically down-regulated ZO-1, Claun-5 and Occludin. Knock-down or inhibition of MMP-2 and MMP-9 expression protected ZO-1, Claun-5 and occludin from degradation and alleviated the permeability of BBB. Our findings suggest that the degradation of tight junction proteins ZO-1, Claun-5 and Occludin by MMP-2 and MMP-9 secreted by leukemic cells constitutes an important mechanism in BBB breakdown in CNS leukemia. These studies provide a potent evidence for future pharmacological treatment to inhibit the CNS involvement in acute leukemia. Disclosures: No relevant conflicts of interest to declare.

Download Full-text