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

Autor: Elbatreek MH; Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands.; Department of Pharmacology and Toxicology, School of Pharmacy, Zagazig University, Zagazig, Egypt., Sadegh S; Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany., Anastasi E; School of Computing, Newcastle University, Newcastle, United Kingdom., Guney E; Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands.; Research Programme on Biomedical Informatics, The Hospital del Mar Medical Research Institute and Pompeu Fabra University, Barcelona, Spain., Nogales C; Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands., Kacprowski T; Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany.; Division of Data Science in Biomedicine, Peter L. Reichertz Institute for Medical Informatics of TU Braunschweig and Hannover Medical School, Brunswick, Germany., Hassan AA; Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands., Teubner A; Central Animal Facility, CPV, Maastricht University, Maastricht, the Netherlands., Huang PH; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.; Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan., Hsu CY; Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.; Taipei Heart Institute, Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan., Schiffers PMH; Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands., Janssen GM; Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands., Kleikers PWM; Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands., Wipat A; School of Computing, Newcastle University, Newcastle, United Kingdom., Baumbach J; Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany.; Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark., De Mey JGR; Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands., Schmidt HHHW; Department of Pharmacology and Personalised Medicine, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2020 Nov 10; Vol. 18 (11), pp. e3000885. Date of Electronic Publication: 2020 Nov 10 (Print Publication: 2020).
DOI: 10.1371/journal.pbio.3000885
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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