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

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  • 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
  • Harald H H W Schmidt

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.

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  • 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 Ja, 2020. "NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype," PLOS Biology, Public Library of Science, vol. 18(11), pages 1-25, November.
  • Handle: RePEc:plo:pbio00:3000885
    DOI: 10.1371/journal.pbio.3000885
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    1. Edward L. Huttlin & Raphael J. Bruckner & Joao A. Paulo & Joe R. Cannon & Lily Ting & Kurt Baltier & Greg Colby & Fana Gebreab & Melanie P. Gygi & Hannah Parzen & John Szpyt & Stanley Tam & Gabriela Z, 2017. "Architecture of the human interactome defines protein communities and disease networks," Nature, Nature, vol. 545(7655), pages 505-509, May.
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