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NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice

AIMS: Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation of superoxide anions by NADPH oxidase Nox1, 2, and 5 reduces nitric oxide availability and can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role of H(2...

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Autores principales: Langbein, Heike, Brunssen, Coy, Hofmann, Anja, Cimalla, Peter, Brux, Melanie, Bornstein, Stefan R., Deussen, Andreas, Koch, Edmund, Morawietz, Henning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900759/
https://www.ncbi.nlm.nih.gov/pubmed/26578199
http://dx.doi.org/10.1093/eurheartj/ehv564
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author Langbein, Heike
Brunssen, Coy
Hofmann, Anja
Cimalla, Peter
Brux, Melanie
Bornstein, Stefan R.
Deussen, Andreas
Koch, Edmund
Morawietz, Henning
author_facet Langbein, Heike
Brunssen, Coy
Hofmann, Anja
Cimalla, Peter
Brux, Melanie
Bornstein, Stefan R.
Deussen, Andreas
Koch, Edmund
Morawietz, Henning
author_sort Langbein, Heike
collection PubMed
description AIMS: Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation of superoxide anions by NADPH oxidase Nox1, 2, and 5 reduces nitric oxide availability and can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role of H(2)O(2) produced by main endothelial isoform Nox4. Therefore, we analysed the impact of genetic deletion of Nox4 on endothelial dysfunction and atherosclerosis in the low-density lipoprotein receptor (Ldlr) knockout model. METHODS AND RESULTS: Ex vivo analysis of endothelial function by Mulvany myograph showed impaired endothelial function in thoracic aorta of Nox4(−/−)/Ldlr(−/−) mice. Further progression of endothelial dysfunction due to high-fat diet increased atherosclerotic plaque burden and galectin-3 staining in Nox4(−/−)/Ldlr(−/−) mice compared with Ldlr(−/−) mice. Under physiological conditions, loss of Nox4 does not influence aortic vascular function. In this setting, loss of Nox4-derived H(2)O(2) production could be partially compensated for by nNOS upregulation. Using an innovative optical coherence tomography approach, we were able to analyse endothelial function by flow-mediated vasodilation in the murine saphenous artery in vivo. This new approach revealed an altered flow-mediated dilation in Nox4(−/−) mice, indicating a role for Nox4 under physiological conditions in peripheral arteries in vivo. CONCLUSIONS: Nox4 plays an important role in maintaining endothelial function under physiological and pathological conditions. Loss of Nox4-derived H(2)O(2) could be partially compensated for by nNOS upregulation, but severe endothelial dysfunction is not reversible. This leads to increased atherosclerosis under atherosclerotic prone conditions.
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spelling pubmed-49007592016-06-10 NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice Langbein, Heike Brunssen, Coy Hofmann, Anja Cimalla, Peter Brux, Melanie Bornstein, Stefan R. Deussen, Andreas Koch, Edmund Morawietz, Henning Eur Heart J Basic Science AIMS: Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation of superoxide anions by NADPH oxidase Nox1, 2, and 5 reduces nitric oxide availability and can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role of H(2)O(2) produced by main endothelial isoform Nox4. Therefore, we analysed the impact of genetic deletion of Nox4 on endothelial dysfunction and atherosclerosis in the low-density lipoprotein receptor (Ldlr) knockout model. METHODS AND RESULTS: Ex vivo analysis of endothelial function by Mulvany myograph showed impaired endothelial function in thoracic aorta of Nox4(−/−)/Ldlr(−/−) mice. Further progression of endothelial dysfunction due to high-fat diet increased atherosclerotic plaque burden and galectin-3 staining in Nox4(−/−)/Ldlr(−/−) mice compared with Ldlr(−/−) mice. Under physiological conditions, loss of Nox4 does not influence aortic vascular function. In this setting, loss of Nox4-derived H(2)O(2) production could be partially compensated for by nNOS upregulation. Using an innovative optical coherence tomography approach, we were able to analyse endothelial function by flow-mediated vasodilation in the murine saphenous artery in vivo. This new approach revealed an altered flow-mediated dilation in Nox4(−/−) mice, indicating a role for Nox4 under physiological conditions in peripheral arteries in vivo. CONCLUSIONS: Nox4 plays an important role in maintaining endothelial function under physiological and pathological conditions. Loss of Nox4-derived H(2)O(2) could be partially compensated for by nNOS upregulation, but severe endothelial dysfunction is not reversible. This leads to increased atherosclerosis under atherosclerotic prone conditions. Oxford University Press 2016-06-07 2015-11-17 /pmc/articles/PMC4900759/ /pubmed/26578199 http://dx.doi.org/10.1093/eurheartj/ehv564 Text en © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Basic Science
Langbein, Heike
Brunssen, Coy
Hofmann, Anja
Cimalla, Peter
Brux, Melanie
Bornstein, Stefan R.
Deussen, Andreas
Koch, Edmund
Morawietz, Henning
NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice
title NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice
title_full NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice
title_fullStr NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice
title_full_unstemmed NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice
title_short NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice
title_sort nadph oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in ldl receptor deficient mice
topic Basic Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900759/
https://www.ncbi.nlm.nih.gov/pubmed/26578199
http://dx.doi.org/10.1093/eurheartj/ehv564
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