Journal
SCIENCE ADVANCES
Volume 7, Issue 6, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abe3706
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Funding
- National Heart, Lung, and Blood Institute [R01 HL132801, R01 HL121797, R01 HL136431, R01 HL147095, R01 HL141917]
- NHLBI Postdoctoral Fellowship [T32 HL098039]
- AHA/Children's Heart Foundation [18CDA34110330]
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Nitric oxide regulates NOTCH pathway through S-nitrosylation to prevent calcific aortic valve disease.
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 an ubiquitin-associated pathway prevents CAVD.
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