In:
PLOS Biology, Public Library of Science (PLoS), Vol. 18, No. 11 ( 2020-11-10), p. e3000885-
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 N ox5 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. N ox5 knock-in (KI) mice represent the first mechanism-based animal model of hypertension.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3000885
DOI:
10.1371/journal.pbio.3000885.g001
DOI:
10.1371/journal.pbio.3000885.g002
DOI:
10.1371/journal.pbio.3000885.g003
DOI:
10.1371/journal.pbio.3000885.t001
DOI:
10.1371/journal.pbio.3000885.s001
DOI:
10.1371/journal.pbio.3000885.s002
DOI:
10.1371/journal.pbio.3000885.s003
DOI:
10.1371/journal.pbio.3000885.s004
DOI:
10.1371/journal.pbio.3000885.s005
DOI:
10.1371/journal.pbio.3000885.s006
DOI:
10.1371/journal.pbio.3000885.s007
DOI:
10.1371/journal.pbio.3000885.s008
DOI:
10.1371/journal.pbio.3000885.s009
DOI:
10.1371/journal.pbio.3000885.s010
DOI:
10.1371/journal.pbio.3000885.s011
DOI:
10.1371/journal.pbio.3000885.s012
DOI:
10.1371/journal.pbio.3000885.s013
DOI:
10.1371/journal.pbio.3000885.s014
DOI:
10.1371/journal.pbio.3000885.s015
DOI:
10.1371/journal.pbio.3000885.s016
DOI:
10.1371/journal.pbio.3000885.s017
DOI:
10.1371/journal.pbio.3000885.s018
DOI:
10.1371/journal.pbio.3000885.r001
DOI:
10.1371/journal.pbio.3000885.r002
DOI:
10.1371/journal.pbio.3000885.r003
DOI:
10.1371/journal.pbio.3000885.r004
DOI:
10.1371/journal.pbio.3000885.r005
DOI:
10.1371/journal.pbio.3000885.r006
DOI:
10.1371/journal.pbio.3000885.r007
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2126773-X
Bookmarklink