HIV-1 Tat Protein-Induced Alterations of ZO-1 Expression are Mediated by Redox-Regulated ERK1/2 Activation
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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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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).”
From Bacterial induction of Snail1 contributes to blood-brain barrier disruption (2015) · cites this paper as [53]
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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
- Publisher
- SAGE Publications
- 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
- bronze
- doi.org
- 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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