Serotonin contribution to cardiac valve degeneration: new insights for novel therapies?. (February 2019)

• Record Type: Journal Article
• Authors: Ayme-Dietrich, Estelle; Lawson, Roland; Da-Silva, Sylvia; Mazzucotelli, Jean Philippe; Monassier, Laurent
• Is Part Of: Pharmacological research. Volume 140(2019)
• Page Start: 33
• Page End: 42
• Publication Date: 2019-02
• Subjects: 5-HIAA 5-hydroxyindoleacetic acid -- 5-HT Serotonin -- CKCS Cavalier King Charles Spaniels -- CHD carcinoid heart disease -- DMVD degenerative mitral valve disease -- ECM extracellular matrix -- EMT endothelial to mesenchymal transition -- ERK Extra-cellular signal-regulated kinases -- HVD heart valve disease -- JNK c-Jun N-terminal kinases -- MAO-A monoamine oxidase A -- MDA 3, 4-methylenedioxyamphetamine -- MDMA 3, 4 MethyleneDioxyMethAmphetamine -- MMP metalloproteinase -- NdF nordexfenfluramine -- NOS3 endothelial nitric oxide synthase -- pCPA para-chlorophenylalanine -- SERT serotonin transporter -- TG2 Transglutaminase 2 -- TGF- β tumor growth factor beta -- Tph1 tryptophane hydroxylase 1 -- WT wild-type; Serotonin -- Valvulopathy -- Cardiac valve lesions -- Remodeling; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.09.009
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Heart valve disease (HVD) is a complex entity made by different pathological processes that ultimately lead to the abnormal structure and disorganization of extracellular matrix proteins resulting to dysfunction of the leaflets. At its final evolutionary step, treatments are limited to the percutaneous or surgical valve replacement, whatever the original cause of the degeneration. Understanding early molecular mechanisms that regulate valve interstitial cells remodeling and disease progression is challenging and could pave the way for future drugs aiming to prevent and/or reverse the process. Some valve degenerative processes such as the carcinoid heart disease, drug-induced valvulopathy and degenerative mitral valve disease in small-breed dogs are clearly linked to serotonin. The carcinoid heart is typically characterized by a right-sided valve dysfunction, observed in patients with carcinoid tumors developed from serotonin-producing gut enterochromaffin cells. Fenfluramine or ergot derivatives were linked to mitral and aortic valve dysfunction and share in common the pharmacological property of being 5-HT2B receptor agonists. Finally, some small-breed dogs, such as the Cavalier King Charles Spaniel are highly prone to degenerative mitral valve disease with a prevalence of 40% at 4 years-old, 70% at 7 years-old and 100% in 10-year-old animals. This degeneration has been linked to high serum serotonin, 5-HT2B receptor overexpression and SERT downregulation. Through the comprehension of serotonergic mechanisms involved into these specific situations, new therapeutic approaches could be extended to HVD in general. More recently, a serotonin dependent/ receptor independent mechanism has been suggested in congenital mitral valve prolapse through the filamin-A serotonylation. This review summarizes clinical and molecular mechanisms linking the serotonergic system and heart valve disease, opening the way for future pharmacological research in the field.