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

Abstract

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.

• Authors: Cécile Oury, Patrick Maréchal, Nathalie Donis, Alexia Hulin, Alexandre Hego, Julien Tridetti, Mai-Linh Nguyen, Raluca Dulgheru, Marianne Fillet, Alain Nchimi, Patrizio Lancellotti
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 11 (Jun 03 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32503311 (Publication Type: Journal Article)

Chemical References

• MicroRNAs
• Transforming Growth Factor beta
• Pergolide
• Serotonin
• Dexfenfluramine
• p38 Mitogen-Activated Protein Kinases
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Administration, Oral
• Animals
• Cell Proliferation
• Cluster Analysis
• Dexfenfluramine (adverse effects)
• Enzyme Activation
• Extracellular Matrix (drug effects)
• Female
• Gene Expression Regulation (drug effects)
• Heart Valve Diseases (chemically induced, metabolism, pathology)
• Homeostasis
• MicroRNAs (genetics)
• Pergolide (adverse effects)
• Rabbits
• Sequence Analysis, RNA
• Serotonin (adverse effects)
• Transcriptome
• Transforming Growth Factor beta (metabolism)
• Tricuspid Valve (drug effects, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)