Cited by 87Barrier Structure and Function StudiesHIV Research and TreatmentDrug Transport and Resistance Mechanisms

HIV-1 Tat Protein-Induced Alterations of ZO-1 Expression are Mediated by Redox-Regulated ERK1/2 Activation

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Pu, Hong, Tian, Jing, Andras, Ibolya E, Hayashi, Kentaro, Flora, Govinder, Hennig, Bernhard, Toborek, Michal·2005·Journal of Cerebral Blood Flow & Metabolism

Abstract

HIV-1 Tat protein plays an important role in inducing monocyte infiltration into the brain and may alter the structure and functions of the blood—brain barrier (BBB). The BBB serves as a frontline defense system, protecting the central nervous system from infected monocytes entering the brain. Therefore, the aim of the present study was to examine the mechanisms of Tat effect on the integrity of the BBB in the mouse brain. Tat was injected into the right hippocampi of C57BL/6 mice and expression of tight junction protein zonula occludens-1 (ZO-1) was determined in control and treated mice. Tat administration resulted in decreased mRNA levels of ZO-1 and marked disruption of ZO-1 continuity. These changes were associated with accumulation of inflammatory cells in brain tissue of Tat-treated mice. Further experiments indicated that Tat-mediated alterations of redox-related signaling may be responsible for decreased ZO-1 expression. Specifically, injections with Tat resulted in activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and pretreatment with U0126, a specific inhibitor of ERK kinase, effectively ameliorated the Tat-induced diminished ZO-1 levels. In addition, administration of N-acetylcysteine (NAC), a precursor of glutathione and a potent antioxidant, attenuated both Tat-induced ERK1/2 activation and alterations in ZO-1 expression. These results indicate that Tat-induced oxidative stress can play an important role in affecting the integrity of the BBB through the ERK1/2 pathway.

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Crossref · 10.1038/sj.jcbfm.9600125

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  • Activation of ERK1/2 results in increased ZO-1 degradation during TBI, decreased ZO-1 and claudin 5 in HIV, and reduced occludin and claudin 5 in ischemic stroke.

    “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).”

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Authors
Pu, H., Tian, J., Andras, I. E., Hayashi, K., Flora, G., Hennig, B., & Toborek, M.
Affiliations
  • University of Kentucky HealthCare (US)
  • University of Kentucky (US)
Corresponding author
Toborek, Michal
Venue
Journal of Cerebral Blood Flow & Metabolism
Published
2005-10
Volume
25
Issue
10
Pages
1325-1335
ISSN
  • 0271-678X (ISSN-L)
  • 1559-7016
OpenAlex
W2014153065
Cited by
87
References
58
Citations by year
2025: 4 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 4 · 2016: 6 · 2015: 3 · 2014: 6 · 2013: 4 · 2012: 1
FWCI
2.59
Type
journal article
Language
en
Open access
Locations
  • Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Johns Hopkins University
  • Toyota Research Institute, North America
  • 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 › Oncology › Drug Transport and Resistance Mechanisms
Keywords
HIV-1 Tat protein, zonula occludens-1, tight junctions, blood-brain barrier integrity, ERK signaling, oxidative stress, N-acetylcysteine, U0126, monocyte infiltration, neuroinflammation, hippocampus, HIV-associated neurocognitive disorders
MeSH terms
Animals, Blood-Brain Barrier, Gene Expression Regulation, Hippocampus, Inflammation, Membrane Proteins, Mice, Inbred C57BL, Oxidation-Reduction, Phosphoproteins, RNA, Messenger, Signal Transduction, Gene Products, tat, Oxidative Stress, Mitogen-Activated Protein Kinase 3, Mice, Zonula Occludens-1 Protein

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