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

Mahmoud H Elbatreek, Sepideh Sadegh, Elisa Anastasi, Emre Guney, Cristian Nogales, Tim Kacprowski, Ahmed A Hassan, Andreas Teubner, Po-Hsun Huang, Chien-Yi Hsu, Paul M H Schiffers, Ger M Janssen, Pamela W M Kleikers, Anil Wipat, Jan Baumbach, Jo G R De Mey and Harald H H W Schmidt

PLOS Biology, 2020, vol. 18, issue 11, 1-25

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.The causes of hypertension are not understood; treatments are symptomatic and prevent only few of the associated risks. This study applies network medicine to identify a subgroup of patients with NADPH oxidase 5-induced uncoupling of nitric oxide synthase as the cause of age-related hypertension, enabling a first-in-class mechanism-based treatment of hypertension.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pbio00:3000885

DOI: 10.1371/journal.pbio.3000885

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