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

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...

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Autores principales: Maier, Nadine, Gatterer, Constantin, Haider, Patrick, Salzmann, Manuel, Kaun, Christoph, Speidl, Walter S., Sunder-Plassmann, Gere, Podesser, Bruno K., Wojta, Johann, Graf, Senta, Lenz, Max, Hohensinner, Philipp J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394417/
https://www.ncbi.nlm.nih.gov/pubmed/34440358
http://dx.doi.org/10.3390/genes12081184
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author Maier, Nadine
Gatterer, Constantin
Haider, Patrick
Salzmann, Manuel
Kaun, Christoph
Speidl, Walter S.
Sunder-Plassmann, Gere
Podesser, Bruno K.
Wojta, Johann
Graf, Senta
Lenz, Max
Hohensinner, Philipp J.
author_facet Maier, Nadine
Gatterer, Constantin
Haider, Patrick
Salzmann, Manuel
Kaun, Christoph
Speidl, Walter S.
Sunder-Plassmann, Gere
Podesser, Bruno K.
Wojta, Johann
Graf, Senta
Lenz, Max
Hohensinner, Philipp J.
author_sort Maier, Nadine
collection PubMed
description 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.
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spelling pubmed-83944172021-08-28 MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease Maier, Nadine Gatterer, Constantin Haider, Patrick Salzmann, Manuel Kaun, Christoph Speidl, Walter S. Sunder-Plassmann, Gere Podesser, Bruno K. Wojta, Johann Graf, Senta Lenz, Max Hohensinner, Philipp J. Genes (Basel) Article 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. MDPI 2021-07-30 /pmc/articles/PMC8394417/ /pubmed/34440358 http://dx.doi.org/10.3390/genes12081184 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Maier, Nadine
Gatterer, Constantin
Haider, Patrick
Salzmann, Manuel
Kaun, Christoph
Speidl, Walter S.
Sunder-Plassmann, Gere
Podesser, Bruno K.
Wojta, Johann
Graf, Senta
Lenz, Max
Hohensinner, Philipp J.
MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease
title MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease
title_full MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease
title_fullStr MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease
title_full_unstemmed MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease
title_short MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease
title_sort mirna let-7a and let-7d are induced by globotriaosylceramide via nf-kb activation in fabry disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394417/
https://www.ncbi.nlm.nih.gov/pubmed/34440358
http://dx.doi.org/10.3390/genes12081184
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