dc.contributor.author | Majumdar, Uddalak | |
dc.contributor.author | Manivannan, Sathiyanarayanan | |
dc.contributor.author | Basu, Madhumita | |
dc.contributor.author | Ueyama, Yukie | |
dc.contributor.author | Blaser, Mark C | |
dc.contributor.author | Cameron, Emily | |
dc.contributor.author | McDermott, Michael R | |
dc.contributor.author | Lincoln, Joy | |
dc.contributor.author | Cole, Susan E | |
dc.contributor.author | Wood, Stephen | |
dc.contributor.author | Aikawa, Elena | |
dc.contributor.author | Lilly, Brenda | |
dc.contributor.author | Garg, Vidu | |
dc.date.accessioned | 2021-02-10T00:37:57Z | |
dc.date.available | 2021-02-10T00:37:57Z | |
dc.date.issued | 2021 | |
dc.identifier.issn | 2375-2548 | |
dc.identifier.doi | 10.1126/sciadv.abe3706 | |
dc.identifier.uri | http://hdl.handle.net/10072/401917 | |
dc.description.abstract | Calcific aortic valve disease (CAVD) is an increasingly prevalent condition, and endothelial dysfunction is implicated in its etiology. We previously identified nitric oxide (NO) as a calcification inhibitor by its activation of NOTCH1, which is genetically linked to human CAVD. Here, we show NO rescues calcification by an S-nitrosylation-mediated mechanism in porcine aortic valve interstitial cells and single-cell RNA-seq demonstrated NO regulates the NOTCH pathway. An unbiased proteomic approach to identify S-nitrosylated proteins in valve cells found enrichment of the ubiquitin-proteasome pathway and implicated S-nitrosylation of USP9X (ubiquitin specific peptidase 9, X-linked) in NOTCH regulation during calcification. Furthermore, S-nitrosylated USP9X was shown to deubiquitinate and stabilize MIB1 for NOTCH1 activation. Consistent with this, genetic deletion of Usp9x in mice demonstrated CAVD and human calcified aortic valves displayed reduced S-nitrosylation of USP9X. These results demonstrate a previously unidentified mechanism by which S-nitrosylation-dependent regulation of a ubiquitin-associated pathway prevents CAVD. | |
dc.description.peerreviewed | Yes | |
dc.language | eng | |
dc.publisher | American Association for the Advancement of Science (AAAS) | |
dc.relation.ispartofpagefrom | eabe3706 | |
dc.relation.ispartofissue | 6 | |
dc.relation.ispartofjournal | Science Advances | |
dc.relation.ispartofvolume | 7 | |
dc.subject.fieldofresearch | Biochemistry and cell biology | |
dc.subject.fieldofresearch | Clinical sciences | |
dc.subject.fieldofresearchcode | 3101 | |
dc.subject.fieldofresearchcode | 3202 | |
dc.title | Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dcterms.bibliographicCitation | Majumdar, U; Manivannan, S; Basu, M; Ueyama, Y; Blaser, MC; Cameron, E; McDermott, MR; Lincoln, J; Cole, SE; Wood, S; Aikawa, E; Lilly, B; Garg, V, Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling, Science Advances, 2021, 7 (6), pp. eabe3706 | |
dcterms.dateAccepted | 2020-12-18 | |
dcterms.license | http://creativecommons.org/licenses/by/4.0/ | |
dc.date.updated | 2021-02-09T23:40:59Z | |
dc.description.version | Version of Record (VoR) | |
gro.rights.copyright | © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S.Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC) | |
gro.hasfulltext | Full Text | |
gro.griffith.author | Wood, Stephen A. | |