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

Autor: 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
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: PLoS Biology, Vol 18, Iss 11, p e3000885 (2020)
Druh dokumentu: article
ISSN: 1544-9173
1545-7885
DOI: 10.1371/journal.pbio.3000885
Popis: 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.
Databáze: Directory of Open Access Journals
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