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

• Published in: PLoS biology Vol. 18; no. 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: Journal Article
• Language: English
• Published: United States Public Library of Science 01.11.2020; Public Library of Science (PLoS)
• 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
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3000885

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.