Factor VIIa releases phosphatidylserine-enriched extracellular vesicles from endothelial cells by activating acid sphingomyelinase.
acid sphingomyelinase
extracellular vesicles
factor VIIa
hemostasis
phosphatidylserine
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
12 2023
12 2023
Historique:
received:
16
03
2023
revised:
05
08
2023
accepted:
23
08
2023
medline:
27
11
2023
pubmed:
25
10
2023
entrez:
24
10
2023
Statut:
ppublish
Résumé
Our recent studies showed that activated factor (F) VII (FVIIa) releases extracellular vesicles (EVs) from the endothelium. FVIIa-released EVs were found to be enriched with phosphatidylserine (PS) and contribute to the hemostatic effect of FVIIa in thrombocytopenia and hemophilia. To investigate mechanisms by which FVIIa induces EV biogenesis and enriches EVs with PS. FVIIa activation of acid sphingomyelinase (aSMase) was evaluated by its translocation to the cell surface. The role of aSMase in the biogenesis of FVIIa-induced EVs and their enrichment with PS was investigated using specific siRNAs and inhibitors of aSMase and its downstream metabolites. Wild-type and aSMase FVIIa activation of aSMase is responsible for both the externalization of PS and the release of EVs in endothelial cells. FVIIa-induced aSMase activation led to ceramide generation and de novo expression of transmembrane protein 16F. Inhibitors of ceramidases, sphingosine kinase, or sphingosine-1-phosphate receptor modulator blocked FVIIa-induced expression of transmembrane protein 16F and PS externalization without interfering with FVIIa release of EVs. In vivo, FVIIa release of EVs was markedly impaired in aSMase Our study identifies a novel mechanism by which FVIIa induces PS externalization and releases PS-enriched EVs.
Sections du résumé
BACKGROUND
Our recent studies showed that activated factor (F) VII (FVIIa) releases extracellular vesicles (EVs) from the endothelium. FVIIa-released EVs were found to be enriched with phosphatidylserine (PS) and contribute to the hemostatic effect of FVIIa in thrombocytopenia and hemophilia.
OBJECTIVE
To investigate mechanisms by which FVIIa induces EV biogenesis and enriches EVs with PS.
METHODS
FVIIa activation of acid sphingomyelinase (aSMase) was evaluated by its translocation to the cell surface. The role of aSMase in the biogenesis of FVIIa-induced EVs and their enrichment with PS was investigated using specific siRNAs and inhibitors of aSMase and its downstream metabolites. Wild-type and aSMase
RESULTS
FVIIa activation of aSMase is responsible for both the externalization of PS and the release of EVs in endothelial cells. FVIIa-induced aSMase activation led to ceramide generation and de novo expression of transmembrane protein 16F. Inhibitors of ceramidases, sphingosine kinase, or sphingosine-1-phosphate receptor modulator blocked FVIIa-induced expression of transmembrane protein 16F and PS externalization without interfering with FVIIa release of EVs. In vivo, FVIIa release of EVs was markedly impaired in aSMase
CONCLUSION
Our study identifies a novel mechanism by which FVIIa induces PS externalization and releases PS-enriched EVs.
Identifiants
pubmed: 37875382
pii: S1538-7836(23)00654-2
doi: 10.1016/j.jtha.2023.08.025
pii:
doi:
Substances chimiques
Factor VIIa
EC 3.4.21.21
Hemostatics
0
Phosphatidylserines
0
Sphingomyelin Phosphodiesterase
EC 3.1.4.12
ASMase, mouse
EC 3.1.4.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3414-3431Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL124055
Pays : United States
Informations de copyright
Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interests There are no competing interests to disclose.