NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage
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Ischemic injury represents the most frequent cause of death and disability, and it remains unclear why, of all body organs, the brain is most sensitive to hypoxia. In many tissues, type 4 NADPH oxidase is induced upon ischemia or hypoxia, converting oxygen to reactive oxygen species. Here, we show in mouse models of ischemia in the heart, brain, and hindlimb that only in the brain does NADPH oxidase 4 (NOX4) lead to ischemic damage. We explain this distinct cellular distribution pattern through cell-specific knockouts. Endothelial NOX4 breaks down the BBB, while neuronal NOX4 leads to neuronal autotoxicity. Vascular smooth muscle NOX4, the common denominator of ischemia within all ischemic organs, played no apparent role. The direct neuroprotective potential of pharmacological NOX4 inhibition was confirmed in an ex vivo model, free of vascular and BBB components. Our results demonstrate that the heightened sensitivity of the brain to ischemic damage is due to an organ-specific role of NOX4 in blood-brain-barrier endothelial cells and neurons. This mechanism is conserved in at least two rodents and humans, making NOX4 a prime target for a first-in-class mechanism-based, cytoprotective therapy in the unmet high medical need indication of ischemic stroke.
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NOX4 is linked to oxidative stress and ROS production in brain injury.
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Self-citation
- Authors
- Casas, A. I., Geuss, E., Kleikers, P. W. M., Mencl, S., Herrmann, A. M., Buendia, I., Egea, J., Meuth, S. G., Lopez, M. G., Kleinschnitz, C., & Schmidt, H. H. H. W.
- Affiliations
- Maastricht University (NL)
- Universitätsklinikum Würzburg (DE)
- Essen University Hospital (DE)
- University of Münster (DE)
- Instituto Teofilo Hernando, Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
- Hospital Universitario de La Princesa (ES)
- Corresponding author
- Kleinschnitz, Christoph
- Schmidt, Harald H. H. W.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-10-31
- Volume
- 114
- Issue
- 46
- Pages
- 12315-12320
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5699031
- OpenAlex
- W2766223740
- Cited by
- 152
- References
- 41
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 16 · 2023: 15 · 2022: 19 · 2021: 28 · 2020: 27 · 2019: 17 · 2018: 9
- FWCI
- 10.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion, cc-by-nc-nd)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- European Research Council. Advanced Investigator Grant (294683 RedMed)
- Deutsche Forschungsgemeinschaft (SFB688)
- Fondo Investigaciones Sanitarias (CP14/00008, PI6/00735)
- Ministerio Economia y Competencia Español (SAF2015-63935R)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- NOX4, NADPH oxidase, blood-brain barrier disruption, cerebral ischemia, ischemic stroke, hypoxia, reactive oxygen species, endothelial cells, vascular smooth muscle cells, neuroprotection
- MeSH terms
- NADPH Oxidase 4, Animals, Benzoxazoles, Blood-Brain Barrier, Brain, Brain Ischemia, Enzyme Inhibitors, Female, Femoral Artery, Gene Expression Regulation, Hindlimb, Humans, Male, Neurons, Organ Specificity, Pyrazoles, Pyridones, Triazoles, Signal Transduction, Myocardial Ischemia, Mice, Knockout, Neuroprotective Agents, Endothelial Cells, Mice, Rats
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