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.
Keywords: BBB; NOX4; endothelium; neurotoxicity; stroke.
Copyright © 2017 the Author(s). Published by PNAS.
Publication types
- Research Support, Non-U.S. Gov't
MeSH terms
- Animals
- Benzoxazoles / pharmacology
- Blood-Brain Barrier / drug effects
- Blood-Brain Barrier / metabolism*
- Blood-Brain Barrier / pathology
- Brain / drug effects
- Brain / enzymology
- Brain / pathology
- Brain Ischemia / enzymology*
- Brain Ischemia / genetics
- Brain Ischemia / pathology
- Brain Ischemia / prevention & control
- Endothelial Cells / drug effects
- Endothelial Cells / metabolism
- Endothelial Cells / pathology
- Enzyme Inhibitors / pharmacology
- Female
- Femoral Artery / injuries
- Gene Expression Regulation
- Hindlimb / blood supply
- Hindlimb / drug effects
- Hindlimb / metabolism
- Hindlimb / pathology
- Humans
- Male
- Mice
- Mice, Knockout
- Myocardial Ischemia / enzymology*
- Myocardial Ischemia / genetics
- Myocardial Ischemia / pathology
- Myocardial Ischemia / prevention & control
- NADPH Oxidase 4 / antagonists & inhibitors
- NADPH Oxidase 4 / genetics*
- NADPH Oxidase 4 / metabolism
- Neurons / drug effects
- Neurons / metabolism
- Neurons / pathology
- Neuroprotective Agents / pharmacology
- Organ Specificity
- Pyrazoles / pharmacology
- Pyridones / pharmacology
- Rats
- Signal Transduction
- Triazoles / pharmacology
Substances
- 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo(4,3-c)pyridine-3,6(2H,5H)-dione
- 3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine
- Benzoxazoles
- Enzyme Inhibitors
- Neuroprotective Agents
- Pyrazoles
- Pyridones
- Triazoles
- NADPH Oxidase 4
- Nox4 protein, mouse
- Nox4 protein, rat