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, Harald H. H. W. Schmidt*

*Corresponding author for this work

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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.

Original languageEnglish
Article number3000885
Number of pages25
JournalPlos Biology
Volume18
Issue number11
DOIs
Publication statusPublished - Nov 2020

Keywords

  • NITRIC-OXIDE SYNTHASE
  • LEFT-VENTRICULAR HYPERTROPHY
  • BLOOD-PRESSURE
  • NADPH OXIDASE
  • OXIDATIVE STRESS
  • RESISTANCE ARTERIES
  • PULMONARY-ARTERIES
  • HYDROGEN-PEROXIDE
  • ELASTIC-MODULUS
  • SMOOTH-MUSCLE

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