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 language | English |
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Article number | 3000885 |
Number of pages | 25 |
Journal | Plos Biology |
Volume | 18 |
Issue number | 11 |
DOIs | |
Publication status | Published - 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