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NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype.
- Source :
- PLoS Biology; 11/10/2020, Vol. 18 Issue 11, p1-25, 25p, 1 Chart, 3 Graphs
- Publication Year :
- 2020
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15449173
- Volume :
- 18
- Issue :
- 11
- Database :
- Complementary Index
- Journal :
- PLoS Biology
- Publication Type :
- Academic Journal
- Accession number :
- 146929274
- Full Text :
- https://doi.org/10.1371/journal.pbio.3000885