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dc.contributor.authorMajumdar, Uddalak
dc.contributor.authorManivannan, Sathiyanarayanan
dc.contributor.authorBasu, Madhumita
dc.contributor.authorUeyama, Yukie
dc.contributor.authorBlaser, Mark C
dc.contributor.authorCameron, Emily
dc.contributor.authorMcDermott, Michael R
dc.contributor.authorLincoln, Joy
dc.contributor.authorCole, Susan E
dc.contributor.authorWood, Stephen
dc.contributor.authorAikawa, Elena
dc.contributor.authorLilly, Brenda
dc.contributor.authorGarg, Vidu
dc.date.accessioned2021-02-10T00:37:57Z
dc.date.available2021-02-10T00:37:57Z
dc.date.issued2021
dc.identifier.issn2375-2548
dc.identifier.doi10.1126/sciadv.abe3706
dc.identifier.urihttp://hdl.handle.net/10072/401917
dc.description.abstractCalcific 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.peerreviewedYes
dc.languageeng
dc.publisherAmerican Association for the Advancement of Science (AAAS)
dc.relation.ispartofpagefromeabe3706
dc.relation.ispartofissue6
dc.relation.ispartofjournalScience Advances
dc.relation.ispartofvolume7
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchClinical sciences
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode3202
dc.titleNitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationMajumdar, 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.dateAccepted2020-12-18
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/
dc.date.updated2021-02-09T23:40:59Z
dc.description.versionVersion 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.hasfulltextFull Text
gro.griffith.authorWood, Stephen A.


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