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

• Published in: International journal of molecular sciences Vol. 21; no. 11; p. 4003
• Main Authors: Oury, Cécile, Maréchal, Patrick, Donis, Nathalie, Hulin, Alexia, Hego, Alexandre, Tridetti, Julien, Nguyen, Mai-Linh, Dulgheru, Raluca, Fillet, Marianne, Nchimi, Alain, Lancellotti, Patrizio
• Format: Journal Article Web Resource
• Language: English
• Published: Switzerland Multidisciplinary Digital Publishing Institute (MDPI) 03-06-2020; MDPI; MDPI AG
• Subjects: Administration, Oral; AMP-Activated Protein Kinases - metabolism; Animals; Cardiovascular & respiratory systems; Cell Proliferation; Cluster Analysis; Dexfenfluramine - adverse effects; Enzyme Activation; Extracellular Matrix - drug effects; Female; Gene Expression Regulation - drug effects; Heart Valve Diseases - chemically induced; Heart Valve Diseases - metabolism; Heart Valve Diseases - pathology; Homeostasis; Human health sciences; metabolism; MicroRNAs - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Pergolide - adverse effects; rabbit model; Rabbits; Sciences de la santé humaine; Sequence Analysis, RNA; serotonergic drugs; Serotonin - adverse effects; Systèmes cardiovasculaire & respiratoire; Transcriptome; Transforming Growth Factor beta - metabolism; Tricuspid Valve - drug effects; Tricuspid Valve - metabolism; valvular heart disease; valvular heart disease; metabolism; rabbit model; serotonergic drugs
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21114003

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.