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

Lookup NU author(s): Dr Elisa Anastasi, Professor Anil Wipat

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Abstract

© 2020 Elbatreek et al.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.

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Author(s): Elbatreek MH, Sadegh S, Anastasi E, Guney E, Nogales C, Kacprowski T, Hassan AA, Teubner A, Huang P-H, Hsu C-Y, Schiffers PMH, Janssen GM, Kleikers PWM, Wipat A, Baumbach J, De Mey JGR, Schmidt HHHW

Publication type: Article

Publication status: Published

Journal: PLoS Biology

Year: 2020

Volume: 18

Issue: 11

Online publication date: 10/11/2020

Acceptance date: 18/09/2020

Date deposited: 15/03/2021

ISSN (print): 1544-9173

ISSN (electronic): 1545-7885

Publisher: Public Library of Science

URL: https://doi.org/10.1371/journal.pbio.3000885

DOI: 10.1371/journal.pbio.3000885

PubMed id: 33170835

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