NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype
Authors: Pamela W M Kleikers
Cristian Nogales
Anil Wipat
Paul M H Schiffers
Emre Guney
Jo G R De Mey
Andreas Teubner
Ger M Janssen
Sepideh Sadegh
Mahmoud H Elbatreek
Jan Baumbach
Tim Kacprowski
Po-Hsun Huang
Harald H H W Schmidt
Ahmed A Hassan
Chien-Yi Hsu
Elisa Anastasi
Journal: PLoS Biology (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Hypertension; Elderly; Endothelium-dependent vasodilation; Reactive oxygen species; NADPH oxidase
Affiliations: 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., Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany., School of Computing, Newcastle University, Newcastle, United Kingdom., Research Programme on Biomedical Informatics, The Hospital del Mar Medical Research Institute and Pompeu Fabra University, Barcelona, Spain., Division of Data Science in Biomedicine, Peter L. Reichertz Institute for Medical Informatics of TU Braunschweig and Hannover Medical School, Brunswick, Germany., Central Animal Facility, CPV, Maastricht University, Maastricht, the Netherlands., Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan., Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan., 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., Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands., Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark.

Abstract:  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. 

Retracted: No

PubPeer comments:
 Did the editors reviewers ever bother to open the supplemental data? I was alerted by this figure suggesting the use of repeated data points. (S1 fig)![file] Here is the underlying data: ![file] , 
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 More of the same in S8![file] , 
 S8 once more![file] , 
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 Would the authors please be so kind to elaborate on these somewhat surprising values? ,