PLoS biology, 2020-11, Vol.18 (11), p.e3000885
2020
Details
- Autor(en) / Beteiligte
- Titel
- NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype
- Ist Teil von
- PLoS biology, 2020-11, Vol.18 (11), p.e3000885
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1545-7885, 1544-9173eISSN: 1545-7885DOI: 10.1371/journal.pbio.3000885Titel-ID: cdi_plos_journals_2479049274
- Format
- –
- Schlagworte
- 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