NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage
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 i...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 46; pp. 12315 - 12320 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
National Academy of Sciences
14.11.2017
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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. |
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AbstractList | 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. Significance Why the brain is uniquely sensitive to hypoxia and which cells are involved is incompletely understood. Here we identify that, upon ischemic stroke, in endothelial cells and neurons the reactive oxygen-forming NADPH oxidase 4 (NOX4) causes breakdown of the BBB and neuronal cell death. This mechanism is unique to the brain and not found in other forms of ischemia in the body. Genetic deletion of either cell type (endothelial or neuronal) or pharmacological inhibition of NOX4 leads to a significant reduction of infarct volume and direct neuroprotection. This mechanism explains the unique vulnerability of the hypoxic brain compared with other organs and provides a clear rationale for first-in-class neuroprotective therapies in stroke. 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. Why the brain is uniquely sensitive to hypoxia and which cells are involved is incompletely understood. Here we identify that, upon ischemic stroke, in endothelial cells and neurons the reactive oxygen-forming NADPH oxidase 4 (NOX4) causes breakdown of the BBB and neuronal cell death. This mechanism is unique to the brain and not found in other forms of ischemia in the body. Genetic deletion of either cell type (endothelial or neuronal) or pharmacological inhibition of NOX4 leads to a significant reduction of infarct volume and direct neuroprotection. This mechanism explains the unique vulnerability of the hypoxic brain compared with other organs and provides a clear rationale for first-in-class neuroprotective therapies in stroke. 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. |
Author | Herrmann, Alexander M. Egea, Javier Casas, Ana I. Kleinschnitz, Christoph Kleikers, Pamela W. M. Geuss, Eva Schmidt, Harald H. H. W. Buendia, Izaskun Meuth, Sven G. Lopez, Manuela G. Mencl, Stine |
Author_xml | – sequence: 1 givenname: Ana I. surname: Casas fullname: Casas, Ana I. organization: Department of Pharmacology and Personalized Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands – sequence: 2 givenname: Eva surname: Geuss fullname: Geuss, Eva organization: Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany – sequence: 3 givenname: Pamela W. M. surname: Kleikers fullname: Kleikers, Pamela W. M. organization: Department of Pharmacology and Personalized Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands – sequence: 4 givenname: Stine surname: Mencl fullname: Mencl, Stine organization: Department of Neurology, University Clinics Essen, D-45147 Essen, Germany – sequence: 5 givenname: Alexander M. surname: Herrmann fullname: Herrmann, Alexander M. organization: Department of Neurology, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany – sequence: 6 givenname: Izaskun surname: Buendia fullname: Buendia, Izaskun organization: Instituto Teofilo Hernando, Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain – sequence: 7 givenname: Javier surname: Egea fullname: Egea, Javier organization: Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain – sequence: 8 givenname: Sven G. surname: Meuth fullname: Meuth, Sven G. organization: Department of Neurology, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany – sequence: 9 givenname: Manuela G. surname: Lopez fullname: Lopez, Manuela G. organization: Instituto Teofilo Hernando, Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain – sequence: 10 givenname: Christoph surname: Kleinschnitz fullname: Kleinschnitz, Christoph organization: Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany – sequence: 11 givenname: Harald H. H. W. surname: Schmidt fullname: Schmidt, Harald H. H. W. organization: Department of Pharmacology and Personalized Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29087944$$D View this record in MEDLINE/PubMed |
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DocumentTitleAlternate | NOX4 explains brain's sensitivity to ischemia |
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Keywords | endothelium NOX4 BBB neurotoxicity stroke |
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Notes | 2C.K. and H.H.H.W.S. contributed equally to this work. Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 6, 2017 (received for review March 28, 2017) 1A.I.C. and E.G. contributed equally to this work. Author contributions: C.K. and H.H.H.W.S. designed research; A.I.C., E.G., P.W.M.K., and S.M. performed research; S.M., A.M.H., I.B., and S.G.M. contributed new reagents/analytic tools; A.I.C., E.G., and S.M. analyzed data; and A.I.C., E.G., P.W.M.K., J.E., M.G.L., C.K., and H.H.H.W.S. wrote the paper. |
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Snippet | 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... Significance Why the brain is uniquely sensitive to hypoxia and which cells are involved is incompletely understood. Here we identify that, upon ischemic... Why the brain is uniquely sensitive to hypoxia and which cells are involved is incompletely understood. Here we identify that, upon ischemic stroke, in... |
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SubjectTerms | 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 |
Title | NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage |
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