No description available.

5-HT2B receptor agonism causes cardiac valvulopathy, a condition characterized by thickening of the heart valves and as a result, regurgitation of blood within the heart. The anti-obesity drug fenfluramine, which was originally prescribed as an anorectic, was withdrawn from the market due to causing cardiac valvulopathy. Fenfluramine, after metabolism by N-dealkylation, produces the metabolite norfenfluramine, which acts as a more potent valvulopathogen. The same was seen with MDMA (ecstasy), a popular drug of abuse, which is metabolized by N-dealkylation to produce MDA, a more potent valvulopathogen. Glennon and co-workers. studied a series of 2,5-dimethoxy-4- substituted phenylisopropylamines (DOX type) hallucinogens and determined their affinities at the three types of 5-HT2 receptors. A high correlation was found between the affinities of these molecules at 5-HT2A and 5-HT2B receptors. Therefore, these hallucinogens have a high possibility of causing valvulopathy, which gives rise to a new class of valvulopathogens. Since certain hallucinogens have the common phenylisopropylamine structural scaffold as that of MDA and norfenfluramine, we conducted 3D-QSAR studies to identify the common structural features of these molecules that are responsible for their high affinities. We were unable to obtain a suitable CoMFA and CoMSIA model for 5-HT2B receptors, but we were able to obtain an internally and externally validated model for 5-HT2A receptor affinities which indicated the hydrophobicity of the substituent at the 4- position was essential for high affinity. Following up with this evidence, we conducted a correlation analysis for the hydrophobicity (π-value) of the 4-position substituent and found a positive correlation between the π-value and the affinity of the molecules. The same results were not observed for the volume of the substituents. We docked the molecules into the 5-HT2B receptor and successfully generated models of the putative interactions made by the DOX molecules and the receptor. In order to compare their binding modes with respect to known valvulopathogens, we also generated models for norfenfluramine and MDA. Our docking results revealed that DOX molecules bind in a more or less similar manner to valvulopathogens MDA and norfenfluramine. Ours is the first in silico model developed for the potent valvulopathogen MDA and the hallucinogenic DOX series of molecules.

L’hypothèse d’un lien entre valvulopathies et surexpression du système sérotoninergique fait suite aux lésions valvulaires observées lors de tumeurs carcinoïdes (taux sanguins de 5-HT élevés) et lors de l’utilisation chronique d’agonistes sérotoninergiques 5-HT2 (comme les dérivés de l’ergot de seigle, les fenfluramines). Le dogme actuel repose sur un effet prolifératif de la sérotonine, activant des cellules résidentes valvulaires, mais ne suffit pas à expliquer la dégénérescence de bioprothèses acellulaires. Nos travaux ont permis d’identifier des cellules progénitrices endothéliales (CD34+/CD309+), exprimant les récepteurs 5-HT2A et 5-HT2B, au sein de lésions valvulaires humaines aortiques et mitrales, quelle que soit l’étiologie de leur dégénérescence. Ils ont permis de mettre en évidence un rôle double de la sérotonine dans la dégénérescence valvulaire : 1) la stimulation des récepteurs 5-HT2B contribue à la mobilisation sanguine des progéniteurs CD34+ (recrutés à partir de la moelle osseuse, et migrant dans le tissu valvulaire), 2) le rôle des récepteurs 5-HT2 dans la transdifférenciation des progéniteurs endothéliaux en cellules activées, au sein de la matrice valvulaire. La suite de ce travail permettra de développer 1) un biomarqueur prédictif d’atteinte valvulaire, dans des populations à haut risque, 2) de développer un modèle cellulaire de valvulopathie pour étudier les mécanismes impliqués dans le remodelage valvulaire et leurs voies de signalisation, et 3) de déterminer des cibles thérapeutiques autour du système sérotoninergique, permettant de ralentir la progression des lésions et retarder l’exérèse chirurgicale, seule alternative actuelle.Abstract / Several studies have established an association between some cardiac valve injuries and overexpression of the serotonergic system. Valve lesions are observed following carcinoid tumours (with high blood levels of 5-HT) and during the chronic use of 5-HT2 serotonergic agonists (ergot derivatives or fenfluramines). The current dogma is based on a mitogenic effect of serotonin, by activating 5-HT2B receptors, leading to resident valvular cells proliferation, but does not explain the degeneration of acellular cardiac bioprosthesis. Our work identified endothelial progenitor cells (CD34 + / CD309 +), expressing 5-HT2A and 5-HT2B receptors, in human aortic and mitral valve lesions, regardless of the etiology of their degeneration. Our work highlights the dual role of serotonin in valvular degeneration: 1) stimulation of the 5-HT2B receptor contributes to blood mobilization of CD34+ progenitors (recruited from the bone marrow, and migrating in the valve tissue), 2) the role of 5-HT2 receptors in the transdifferentiation of endothelial progenitor cells in activated valvular cells. The results of this work could drive to the development of 1) a predictive biomarker of cardiac valve injuries in high-risk populations, 2) a model to study heart valve disease cellular and molecular mechanisms, and 3) identify therapeutic targets around the serotonergic system, to slower the progression of the lesions and delay surgical replacement, the only current alternative.