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Signaling Mechanisms of HIV-1 Tat-Induced Alterations of Claudin-5 Expression in Brain Endothelial Cells
Abstract
Exposure of brain microvascular endothelial cells (BMEC) to human immunodeficiency virus-1 (HIV-1) Tat protein can decrease expression and change distribution of tight junction proteins, including claudin-5. Owing to the importance of claudin-5 in maintaining the blood–brain barrier (BBB) integrity, the present study focused on the regulatory mechanisms of Tat-induced alterations of claudin-5 mRNA and protein levels. Real-time reverse-transcription-polymerase chain reaction revealed that claudin-5 mRNA was markedly diminished in BMEC exposed to Tat. However, U0126 (an inhibitor of mitogen-activated protein kinase kinase1/2, MEK1/2) protected against this effect. In addition, inhibition of the vascular endothelial growth factor receptor type 2 (VEGFR-2) by SU1498, phosphatidylinositol-3 kinase (PI-3 K) by LY294002, nuclear factor-κB (NF-κB) by peptide SN50, and intracellular calcium by BAPTA/AM partially prevented Tat-mediated alterations in claudin-5 protein levels and immunoreactivity patterns. In contrast, inhibition of protein kinase C did not affect claudin-5 expression in Tat-treated cells. The present findings indicate that activation of VEGFR-2 and multiple redox-regulated signal transduction pathways are involved in Tat-induced alterations of claudin-5 expression. Because claudins constitute the major backbone of tight junctions, the present data are relevant to the disturbances of the BBB in the course of HIV-1 infection.
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“Activation of ERK1/2 results in increased ZO-1 degradation during traumatic brain injury (51), decreased ZO-1 and claudin 5 expression in brain endothelium during HIV infection (52,53), and reduced occludin and claudin 5 expression in BBB endothelium during ischemic stroke (54).”
From Bacterial induction of Snail1 contributes to blood-brain barrier disruption (2015) · cites this paper as [52]
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Metadata
- Authors
- András, I. E., Pu, H., Tian, J., Deli, M. A., Nath, A., Hennig, B., & Toborek, M.
- Affiliations
- Department of Surgery, University of Kentucky, Lexington, Kentucky, USA
- University of Kentucky (US)
- HUN-REN Szegedi Biológiai Kutatóközpont (HU)
- Johns Hopkins University (US)
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2005-09
- Volume
- 25
- Issue
- 9
- Pages
- 1159-1170
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- OpenAlex
- W1973010584
- Cited by
- 121
- References
- 59
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 3 · 2017: 6 · 2016: 8 · 2015: 4 · 2014: 7 · 2013: 7 · 2012: 9
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r21aa013843-03)
- National Institute on Alcohol Abuse and Alcoholism (AA 013843)
- National Institute of Mental Health (MH 63022, R01MH063022)
- National Institute of Neurological Disorders and Stroke (R01NS039254, NS-39254)
- National Institute of Environmental Health Sciences (P42ES007380)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- HIV-1 Tat protein, claudin-5, brain microvascular endothelial cells, blood-brain barrier, tight junction proteins, VEGFR2 signaling, PI3K signaling, NF-κB signaling, MEK1/2, redox signaling, intracellular calcium, protein kinase C, HIV-associated neurocognitive disorders
- MeSH terms
- Animals, Brain Chemistry, Calcium, Cells, Cultured, Chelating Agents, Membrane Proteins, Microscopy, Fluorescence, Genes, ras, RNA, Messenger, Blotting, Western, Signal Transduction, HIV-1, Down-Regulation, Gene Products, tat, NF-kappa B, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Vascular Endothelial Growth Factor Receptor-2, Endothelial Cells, Rats, tat Gene Products, Human Immunodeficiency Virus, Claudin-5
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