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.
Highlights
Valvular heart diseases (VHD) have been associated with the use of amphetaminic anorectic drugs, including fenfluramine, benfluorex, and dexfenfluramine, and of ergot derivatives, such as those used for the treatment of Parkinson disease, pergolide and cabergoline [1,2,3]
Serotonin (Figure 1B,U) and pergolide induced the formation of chondroid metaplasia in aortic hinge of all rabbits (Figure 1C,U) (p = 0.05), while it occurred in two rabbits out of three after dexfenfluramine treatment (Figure 1D,U) (p = 0.2)
tricuspid valve (TV) leaflets of pergolide- and dexfenfluramine-treated rabbits showed areas of connective tissue growth factor (CTGF) that were not observed in the serotonin-treated group (Supplementary Material online, Figure S1A)
Summary
Valvular heart diseases (VHD) have been associated with the use of amphetaminic anorectic drugs, including fenfluramine, benfluorex, and dexfenfluramine, and of ergot derivatives, such as those used for the treatment of Parkinson disease, pergolide and cabergoline [1,2,3]. The mechanisms responsible for the development of drug-induced VHD have not been fully elucidated yet. Animal studies have pointed to serotonin and its 5-HT2B receptor as a possible common pathogenic link between drug-induced VHD and carcinoid heart valve diseases, characterized by excess of plasma serotonin secreted by neuroendocrine tumors [4]. We previously showed that long-term oral administration of high-dose serotonin causes VHD [5]. Histological examination indicated carcinoid-like plaques, thickened valves, and chondroid metaplasia, confirming that serotonin signaling could be involved in the development of VHD. Whether this mechanism applies to the pathogenesis of other drug-induced VHD remains undetermined
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