Inhibition and down regulation of the serotonin transporter contribute to the progression of degenerative mitral regurgitation

Levy, R. J.; Fitzpatrick, E.; Castillero, E.; Shukla,, H. J.; Inamdar,, V. V.; Aghali, A. E.; Grau, J. B.; Rioux, N.; Salvati, E.; Keeney, S. J.; Nissim, I.; Gorman, R. C. C.; Rauova, L.; Stachelek, S. J.; Brown, C. R.; Krieger, A. M.; Ferrari, G.

doi:10.1101/2020.03.10.985382

bioRxiv · 10.1101/2020.03.10.985382

Inhibition and down regulation of the serotonin transporter contribute to the progression of degenerative mitral regurgitation

Levy, R. J.·Fitzpatrick, E.·Castillero, E.·Shukla,, H. J.·Inamdar,, V. V.·Aghali, A. E.·Grau, J. B.·Rioux, N.·Salvati, E.·Keeney, S. J.·Nissim, I.·Gorman, R. C. C.·Rauova, L.·Stachelek, S. J.·Brown, C. R.·Krieger, A. M.·Ferrari, G.

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Abstract

AimsHeart valve disease attributed to serotonin (5HT) has been observed with 5HT-secreting carcinoid tumors and in association with medications, such as the diet drug, Dexfenfluoramine, a serotonin transporter (SLC6A4) inhibitor and 5HT receptor (HTR) 2B agonist. HTR2B signaling upregulates TGF{beta}-1 resulting in increased production of extracellular matrix proteins. SLC6A4 internalizes 5HT, limiting HTR signaling. Selective 5HT reuptake inhibitors (SSRI), widely used antidepressants, target SLC6A4, thus enhancing HTR signaling. However, 5HT and SLC6A4 mechanisms have not been previously associated with degenerative mitral regurgitation (MR). The present studies investigated the hypothesis that both dysregulation of SLC6A4 and inhibition of SLC6A4 contribute to the pathophysiology of MR. Methods and ResultsHere we report SLC6A4 related studies of 225 patients with MR requiring surgery. A multivariate analysis showed that SSRI use in MR patients was associated with surgery at a younger age, indicating more rapidly progressive MR (p=0.0183); this was confirmed in a national dataset (p<0.001). Aspirin use by MR patients was associated with surgery at an older age (p=0.0055). Quantitative reverse transcriptase PCR of MR leaflet RNA from 44 patients, and 20 normal mitral leaflets from heart transplant recipients, demonstrated down regulation in MR of both SLC6A4 and vesicular monoamine transporter-2 (SLC18A2), that packages 5HT (p<0.001). Human mitral valve interstitial cells cultivated with Fluoxetine, a SSRI, demonstrated down regulation of SLC6A4 and upregulation of HTR2B, compared to untreated, in cells from both normal and MR leaflets. Platelet 5HT studies in healthy subjects without heart disease used ADP-induced activation to model MR-associated activation. Fluoxetine significantly increased platelet activation and plasma 5HT levels, while Aspirin inhibited ADP platelet activation. ConclusionsDown regulation and inhibition of SLC6A4 influences MR through enhanced HTR signaling. SSRI may further influence MR through inhibition and down regulation of SLC6A4, upregulation of HTR2B, and increased platelet release of 5HT. Translational PerspectiveDegenerative mitral valve regurgitation (MR) affects millions, and there is no medical therapy for this disease. MR becomes progressively worse, and for severe MR, the only option is cardiac surgery. Serotonin (5HT) is best known as a neurotransmitter. However, 5HT secreting carcinoid tumors cause a cardiac valve disorder in many cases, and 5HT related medications, such as the diet drug Fenfluoramine, have been associated with the development of cardiac valve disease. The present paper presents evidence that diminished serotonin transporter (SLC6A4) expression and inhibition, lead to increased 5HT receptor signaling, contributing to the progression of MR.

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Levy, R. J., Fitzpatrick, E., Castillero, E., Shukla,, H. J., Inamdar,, V. V., Aghali, A. E., Grau, J. B., Rioux, N., Salvati, E., Keeney, S. J., Nissim, I., Gorman, R. C. C., Rauova, L., Stachelek, S. J., Brown, C. R., Krieger, A. M., Ferrari, G.. 2020-03-11. Inhibition and down regulation of the serotonin transporter contribute to the progression of degenerative mitral regurgitation. https://doi.org/10.1101/2020.03.10.985382

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