Acid sphingomyelinase promotes SGK1-dependent vascular calcification.
Amitriptyline
/ pharmacology
Animals
Cell Transdifferentiation
Cells, Cultured
Ceramides
/ metabolism
Chondrogenesis
/ drug effects
Fendiline
/ pharmacology
Humans
Immediate-Early Proteins
/ metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular
/ drug effects
Osteogenesis
/ drug effects
Phosphates
/ pharmacology
Protein Serine-Threonine Kinases
/ metabolism
Sphingomyelin Phosphodiesterase
/ pharmacology
Vascular Calcification
/ pathology
acid sphingomyelinase
ceramide
phosphate
serum- and glucocorticoid-inducible kinase 1
vascular calcification
vascular smooth muscle cells
Journal
Clinical science (London, England : 1979)
ISSN: 1470-8736
Titre abrégé: Clin Sci (Lond)
Pays: England
ID NLM: 7905731
Informations de publication
Date de publication:
12 02 2021
12 02 2021
Historique:
received:
07
09
2020
revised:
07
01
2021
accepted:
21
01
2021
pubmed:
23
1
2021
medline:
8
9
2021
entrez:
22
1
2021
Statut:
ppublish
Résumé
In chronic kidney disease (CKD), hyperphosphatemia is a key factor promoting medial vascular calcification, a common complication associated with cardiovascular events and high mortality. Vascular calcification involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs), but the complex signaling events inducing pro-calcific pathways are incompletely understood. The present study investigated the role of acid sphingomyelinase (ASM)/ceramide as regulator of VSMC calcification. In vitro, both, bacterial sphingomyelinase and phosphate increased ceramide levels in VSMCs. Bacterial sphingomyelinase as well as ceramide supplementation stimulated osteo-/chondrogenic transdifferentiation during control and high phosphate conditions and augmented phosphate-induced calcification of VSMCs. Silencing of serum- and glucocorticoid-inducible kinase 1 (SGK1) blunted the pro-calcific effects of bacterial sphingomyelinase or ceramide. Asm deficiency blunted vascular calcification in a cholecalciferol-overload mouse model and ex vivo isolated-perfused arteries. In addition, Asm deficiency suppressed phosphate-induced osteo-/chondrogenic signaling and calcification of cultured VSMCs. Treatment with the functional ASM inhibitors amitriptyline or fendiline strongly blunted pro-calcific signaling pathways in vitro and in vivo. In conclusion, ASM/ceramide is a critical upstream regulator of vascular calcification, at least partly, through SGK1-dependent signaling. Thus, ASM inhibition by repurposing functional ASM inhibitors to reduce the progression of vascular calcification during CKD warrants further study.
Identifiants
pubmed: 33479769
pii: 227637
doi: 10.1042/CS20201122
pmc: PMC7859357
doi:
Substances chimiques
Ceramides
0
Immediate-Early Proteins
0
Phosphates
0
Amitriptyline
1806D8D52K
Protein Serine-Threonine Kinases
EC 2.7.11.1
serum-glucocorticoid regulated kinase
EC 2.7.11.1
Sphingomyelin Phosphodiesterase
EC 3.1.4.12
Fendiline
S253D559A8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
515-534Informations de copyright
© 2021 The Author(s).
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