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

  • Harald H.H.W. Schmidt (Creator)
  • Mahmoud H. Elbatreek (Creator)
  • Sepideh Sadegh (Creator)
  • Elisa Anastasi (Creator)
  • Emre Guney (Creator)
  • Cristian Nogales (Creator)
  • Tim Kacprowski (Creator)
  • Ayon Ahmed Hassan (Creator)
  • Andreas Teubner (Creator)
  • Po Hsun Huang (Creator)
  • Chien-Yi Hsu (Creator)
  • Paul M.H. Schiffers (Creator)
  • Ger M. Janssen (Creator)
  • Pamela W.M. Kleikers (Creator)
  • Anil Wipat (Creator)
  • Jan Baumbach (Creator)
  • Jo G.R. De Mey (Creator)
  • Maastricht University (Contributor)



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.
Date made available2022

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