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

Mahmoud H. Elbatreek, Sepideh Sadegh, Elisa Anastasi, Emre Guney, Cristian Nogales, Tim Kacprowski, Ahmed A. Hassan, Andreas Teubner, Po Hsun Huang, Chien Yi Hsu, Paul M.H. Schiffers, Ger M. Janssen, Pamela W.M. Kleikers, Anil Wipat, Jan Baumbach, Jo G.R. De Mey, Harald H.H.W. Schmidt

研究成果: 雜誌貢獻文章同行評審

8 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
文章編號e3000885
期刊PLoS Biology
18
發行號11
DOIs
出版狀態已發佈 - 11月 10 2020

ASJC Scopus subject areas

  • 神經科學 (全部)
  • 生物化學、遺傳與分子生物學 (全部)
  • 免疫學與微生物學 (全部)
  • 農業與生物科學 (全部)

指紋

深入研究「NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype」主題。共同形成了獨特的指紋。

引用此