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MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease

Authors :
Philipp J. Hohensinner
Patrick Haider
Gere Sunder-Plassmann
Senta Graf
Manuel Salzmann
Constantin Gatterer
Max Lenz
Christoph Kaun
Bruno K. Podesser
Walter S. Speidl
Johann Wojta
Nadine Maier
Source :
Genes, Vol 12, Iss 1184, p 1184 (2021), Genes, Volume 12, Issue 8
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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.

Details

Language :
English
ISSN :
20734425
Volume :
12
Issue :
1184
Database :
OpenAIRE
Journal :
Genes
Accession number :
edsair.doi.dedup.....a643de22e5f6c6bfcd2796429cc97dcc