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Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling

Several clinical reports indicate that the use of amphetaminic anorectic drugs or ergot derivatives could cause valvular heart disease (VHD). We sought to investigate whether valvular lesions develop in response to long-term oral administration of these drugs and to identify drug-targeted biological...

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Autores principales: Oury, Cécile, Maréchal, Patrick, Donis, Nathalie, Hulin, Alexia, Hego, Alexandre, Tridetti, Julien, Nguyen, Mai-Linh, Dulgheru, Raluca, Fillet, Marianne, Nchimi, Alain, Lancellotti, Patrizio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312197/
https://www.ncbi.nlm.nih.gov/pubmed/32503311
http://dx.doi.org/10.3390/ijms21114003
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author Oury, Cécile
Maréchal, Patrick
Donis, Nathalie
Hulin, Alexia
Hego, Alexandre
Tridetti, Julien
Nguyen, Mai-Linh
Dulgheru, Raluca
Fillet, Marianne
Nchimi, Alain
Lancellotti, Patrizio
author_facet Oury, Cécile
Maréchal, Patrick
Donis, Nathalie
Hulin, Alexia
Hego, Alexandre
Tridetti, Julien
Nguyen, Mai-Linh
Dulgheru, Raluca
Fillet, Marianne
Nchimi, Alain
Lancellotti, Patrizio
author_sort Oury, Cécile
collection PubMed
description Several clinical reports indicate that the use of amphetaminic anorectic drugs or ergot derivatives could cause valvular heart disease (VHD). We sought to investigate whether valvular lesions develop in response to long-term oral administration of these drugs and to identify drug-targeted biological processes that may lead to VHD. Treatment of New Zealand White rabbits with pergolide, dexfenfluramine, or high-dose serotonin for 16 weeks induced valvular alterations characterized by extracellular matrix remodeling. Transcriptome profiling of tricuspid valves using RNA sequencing revealed distinct patterns of differentially expressed genes (DEGs) that clustered according to the different treatments. Genes that were affected by the three treatments were functionally enriched for reduced cell metabolism processes. The two drugs yielded more changes in gene expression than serotonin and shared most of the DEGs. These DEGs were mostly enriched for decreased biosynthetic processes, increased cell-matrix interaction, and cell response to growth factors, including TGF-β, which was associated with p38 MAPK activation. Treatment with pergolide specifically affected genes involved in homeostasis, which was corroborated by the activation of the master regulator of cell energy homeostasis, AMPK-α, as well as decreased levels of metabolism-related miR-107. Thus, both pergolide and dexfenfluramine may cause VHD through valve metabolic reprogramming and matrix remodeling.
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spelling pubmed-73121972020-06-26 Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling Oury, Cécile Maréchal, Patrick Donis, Nathalie Hulin, Alexia Hego, Alexandre Tridetti, Julien Nguyen, Mai-Linh Dulgheru, Raluca Fillet, Marianne Nchimi, Alain Lancellotti, Patrizio Int J Mol Sci Article Several clinical reports indicate that the use of amphetaminic anorectic drugs or ergot derivatives could cause valvular heart disease (VHD). We sought to investigate whether valvular lesions develop in response to long-term oral administration of these drugs and to identify drug-targeted biological processes that may lead to VHD. Treatment of New Zealand White rabbits with pergolide, dexfenfluramine, or high-dose serotonin for 16 weeks induced valvular alterations characterized by extracellular matrix remodeling. Transcriptome profiling of tricuspid valves using RNA sequencing revealed distinct patterns of differentially expressed genes (DEGs) that clustered according to the different treatments. Genes that were affected by the three treatments were functionally enriched for reduced cell metabolism processes. The two drugs yielded more changes in gene expression than serotonin and shared most of the DEGs. These DEGs were mostly enriched for decreased biosynthetic processes, increased cell-matrix interaction, and cell response to growth factors, including TGF-β, which was associated with p38 MAPK activation. Treatment with pergolide specifically affected genes involved in homeostasis, which was corroborated by the activation of the master regulator of cell energy homeostasis, AMPK-α, as well as decreased levels of metabolism-related miR-107. Thus, both pergolide and dexfenfluramine may cause VHD through valve metabolic reprogramming and matrix remodeling. MDPI 2020-06-03 /pmc/articles/PMC7312197/ /pubmed/32503311 http://dx.doi.org/10.3390/ijms21114003 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Oury, Cécile
Maréchal, Patrick
Donis, Nathalie
Hulin, Alexia
Hego, Alexandre
Tridetti, Julien
Nguyen, Mai-Linh
Dulgheru, Raluca
Fillet, Marianne
Nchimi, Alain
Lancellotti, Patrizio
Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling
title Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling
title_full Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling
title_fullStr Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling
title_full_unstemmed Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling
title_short Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling
title_sort dexfenfluramine and pergolide cause heart valve disease via valve metabolic reprogramming and ongoing matrix remodeling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312197/
https://www.ncbi.nlm.nih.gov/pubmed/32503311
http://dx.doi.org/10.3390/ijms21114003
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