NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype

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• dc.contributor.author Elbatreek, Mahmoud
• dc.contributor.author Sadegh, Sepideh
• dc.contributor.author Anastasi, Elisa
• dc.contributor.author Guney, Emre
• dc.contributor.author Nogales, Cristian
• dc.contributor.author Kacprowski, Tim
• dc.contributor.author Hassan, Ahmed
• dc.contributor.author Teubner, Andreas
• dc.contributor.author Huang, Po-Hsun
• dc.contributor.author Hsu, Chien-Yi
• dc.contributor.author Schiffers, Paul M. H.
• dc.contributor.author Janssen, Ger M.
• dc.contributor.author Kleikers, Pamela W. M.
• dc.contributor.author Wipat, Anil
• dc.contributor.author Baumbach, Jan
• dc.contributor.author De Mey, Jo G.R.
• dc.contributor.author Schmidt, Harald H.H.W.
• dc.date.accessioned 2022-01-28T08:01:09Z
• dc.date.available 2022-01-28T08:01:09Z
• dc.date.issued 2020
• dc.description.abstract Hypertension is the most important cause of death and disability in the elderly. In 9 out of 10 cases, the molecular cause, however, is unknown. One mechanistic hypothesis involves impaired endothelium-dependent vasodilation through reactive oxygen species (ROS) formation. Indeed, ROS forming NADPH oxidase (Nox) genes associate with hypertension, yet target validation has been negative. We re-investigate this association by molecular network analysis and identify NOX5, not present in rodents, as a sole neighbor to human vasodilatory endothelial nitric oxide (NO) signaling. In hypertensive patients, endothelial microparticles indeed contained higher levels of NOX5-but not NOX1, NOX2, or NOX4-with a bimodal distribution correlating with disease severity. Mechanistically, mice expressing human Nox5 in endothelial cells developed-upon aging-severe systolic hypertension and impaired endothelium-dependent vasodilation due to uncoupled NO synthase (NOS). We conclude that NOX5-induced uncoupling of endothelial NOS is a causal mechanism and theragnostic target of an age-related hypertension endotype. Nox5 knock-in (KI) mice represent the first mechanism-based animal model of hypertension.
• dc.format.mimetype application/pdf
• dc.identifier.citation Elbatreek MH, Sadegh S, Anastasi E, Guney E, Nogales C, Kacprowski T, et al. NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype. PLoS Biol. 2020 Nov 10; 18(11): e3000885. DOI: 10.1371/journal.pbio.3000885
• dc.identifier.doi http://dx.doi.org/10.1371/journal.pbio.3000885
• dc.identifier.issn 1544-9173
• dc.identifier.uri http://hdl.handle.net/10230/52349
• dc.language.iso eng
• dc.publisher Public Library of Science (PLoS)
• dc.rights Copyright © 2020 Elbatreek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Hipertensió
• dc.subject.other Persones grans -- Mortalitat
• dc.subject.other Genètica
• dc.title NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion