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

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...

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Bibliographic Details
Published in:PLoS biology 2020-11, Vol.18 (11), p.e3000885
Main Authors: Elbatreek, Mahmoud H, Sadegh, Sepideh, Anastasi, Elisa, Guney, Emre, Nogales, Cristian, Kacprowski, Tim, Hassan, Ahmed A, Teubner, Andreas, Huang, Po-Hsun, Hsu, Chien-Yi, Schiffers, Paul M H, Janssen, Ger M, Kleikers, Pamela W M, Wipat, Anil, Baumbach, Jan, De Mey, Jo G R, Schmidt, Harald H H W
Format: Article
Language:English
Subjects:
Adult
Age Factors
Aged
Aging
Algorithms
Animals
Antioxidants
Biology and Life Sciences
Blood pressure
Blood vessels
Computer applications
CYBB protein
Cyclic GMP
Diabetes mellitus
Disease
Endothelial Cells
Endothelium, Vascular
Enzyme-linked immunosorbent assay
Enzymes
Female
Gene Knock-In Techniques - methods
Genes
Guanylate cyclase
Heart attacks
Humans
Hypertension
Hypertension - genetics
Hypertension - metabolism
Hypertension - physiopathology
Hypotheses
Identification methods
Isoforms
Kinases
Male
Medicine and Health Sciences
Membrane Proteins - genetics
Mice
Microparticles
Middle Aged
Modularity
Modules
Muscles
NAD(P)H oxidase
NADPH Oxidase 5 - genetics
NADPH Oxidase 5 - metabolism
NADPH Oxidases - genetics
NADPH Oxidases - metabolism
Nephropathy
Nitric oxide
Nitric Oxide - genetics
Nitric Oxide - metabolism
Nitric Oxide Synthase - genetics
Nitric Oxide Synthase - metabolism
Nitric Oxide Synthase Type III - genetics
Nitric Oxide Synthase Type III - metabolism
Nitric-oxide synthase
Optimization
Oxidative stress
Patients
Phosphodiesterase
Physical Sciences
Protein kinase
Protein kinase G
Proteins
Reactive Oxygen Species
Research and Analysis Methods
Smooth muscle
Superoxide dismutase
Vasodilation
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Summary: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.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3000885