MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease.
Fabry disease
Gb3
NF-κB
inflammation
Journal
Genes
ISSN: 2073-4425
Titre abrégé: Genes (Basel)
Pays: Switzerland
ID NLM: 101551097
Informations de publication
Date de publication:
30 07 2021
30 07 2021
Historique:
received:
22
06
2021
revised:
22
07
2021
accepted:
26
07
2021
entrez:
27
8
2021
pubmed:
28
8
2021
medline:
11
2
2022
Statut:
epublish
Résumé
Fabry disease is a hereditary genetic defect resulting in reduced activity of the enzyme α-galactosidase-A and the accumulation of globotriaosylceramide (Gb3) in body fluids and cells. Gb3 accumulation was especially reported for the vascular endothelium in several organs. Three Fabry disease patients were screened using a micro-RNA screen. An in vitro approach in human endothelial cells was used to determine miRNA regulation by Gb3. In a micro-RNA screen of three Fabry patients undergoing enzyme replacement therapy, we found that miRNAs let-7a and let-7d were significantly increased after therapy. We demonstrate in vitro in endothelial cells that Gb3 induced activation of NF-κB and activated downstream targets. In addition, NF-κB activity directly reduced let-7a and let-7d miRNA expression as inhibiting NF-kB nuclear entry abolished the Gb3 effects. We suggest that let-7a and let-7d are potential markers for enzyme activity and inflammation in Fabry disease patients.
Sections du résumé
BACKGROUND
Fabry disease is a hereditary genetic defect resulting in reduced activity of the enzyme α-galactosidase-A and the accumulation of globotriaosylceramide (Gb3) in body fluids and cells. Gb3 accumulation was especially reported for the vascular endothelium in several organs.
METHODS
Three Fabry disease patients were screened using a micro-RNA screen. An in vitro approach in human endothelial cells was used to determine miRNA regulation by Gb3.
RESULTS
In a micro-RNA screen of three Fabry patients undergoing enzyme replacement therapy, we found that miRNAs let-7a and let-7d were significantly increased after therapy. We demonstrate in vitro in endothelial cells that Gb3 induced activation of NF-κB and activated downstream targets. In addition, NF-κB activity directly reduced let-7a and let-7d miRNA expression as inhibiting NF-kB nuclear entry abolished the Gb3 effects.
CONCLUSION
We suggest that let-7a and let-7d are potential markers for enzyme activity and inflammation in Fabry disease patients.
Identifiants
pubmed: 34440358
pii: genes12081184
doi: 10.3390/genes12081184
pmc: PMC8394417
pii:
doi:
Substances chimiques
MicroRNAs
0
NF-kappa B
0
Trihexosylceramides
0
mirnlet7 microRNA, human
0
globotriaosylceramide
71965-57-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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