Elbatreek, MahmoudSadegh, SepidehAnastasi, ElisaGuney, EmreNogales, CristianKacprowski, TimHassan, AhmedTeubner, AndreasHuang, Po-HsunHsu, Chien-YiSchiffers, Paul M. H.Janssen, Ger M.Kleikers, Pamela W. M.Wipat, AnilBaumbach, JanDe Mey, Jo G.R.Schmidt, Harald H.H.W.2022-01-282022-01-282020Elbatreek 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.30008851544-9173http://hdl.handle.net/10230/52349Hypertension 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.application/pdfengCopyright © 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.HipertensióPersones grans -- MortalitatGenèticainfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1371/journal.pbio.3000885info:eu-repo/semantics/openAccess