NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage

Ana I. Casas, Eva Geuss, Pamela W. M. Kleikers, Stine Mencl, Alexander M. Herrmann, Izaskun Buendia, Javier Egea, Sven G. Meuth, Manuela G. Lopez, Christoph Kleinschnitz*, Harald H. H. W. Schmidt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Pages (from-to)12315-12320
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number46
DOIs
Publication statusPublished - 14 Nov 2017

Keywords

  • NOX4
  • stroke
  • BBB
  • neurotoxicity
  • endothelium
  • NADPH OXIDASE
  • OXIDATIVE STRESS
  • ISCHEMIA/REPERFUSION INJURY
  • THERAPEUTIC TARGETS
  • UP-REGULATION
  • NEUROPROTECTION
  • ANGIOGENESIS
  • INHIBITION
  • STROKE

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