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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 46; pp. 12315 - 12320
• Main Authors: Casas, Ana I., Geuss, Eva, Kleikers, Pamela W. M., Mencl, Stine, Herrmann, Alexander M., Buendia, Izaskun, Egea, Javier, Meuth, Sven G., Lopez, Manuela G., Kleinschnitz, Christoph, Schmidt, Harald H. H. W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.11.2017
• Subjects: Animal models; Animal tissues; Animals; Benzoxazoles - pharmacology; Biological Sciences; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Brain; Brain - drug effects; Brain - enzymology; Brain - pathology; Brain damage; Brain injury; Brain Ischemia - enzymology; Brain Ischemia - genetics; Brain Ischemia - pathology; Brain Ischemia - prevention & control; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Enzyme Inhibitors - pharmacology; Female; Femoral Artery - injuries; Gene Expression Regulation; Heart; Hindlimb - blood supply; Hindlimb - drug effects; Hindlimb - metabolism; Hindlimb - pathology; Humans; Hypoxia; Ischemia; Male; Mice; Mice, Knockout; Muscles; Myocardial Ischemia - enzymology; Myocardial Ischemia - genetics; Myocardial Ischemia - pathology; Myocardial Ischemia - prevention & control; NAD(P)H oxidase; NADPH Oxidase 4 - antagonists & inhibitors; NADPH Oxidase 4 - genetics; NADPH Oxidase 4 - metabolism; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotection; Neuroprotective Agents - pharmacology; NOX4 protein; Organ Specificity; Organs; Oxidase; Pharmacology; Pyrazoles - pharmacology; Pyridones - pharmacology; Rats; Reactive oxygen species; Rodents; Sensitivity; Signal Transduction; Smooth muscle; Stroke; Toxicity; Triazoles - pharmacology; endothelium; NOX4; BBB; neurotoxicity; stroke
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1705034114

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.