biostudies-literatureCastillero ENHLBI NIH HHSNCI NIH HHSeadc9606https://www.ebi.ac.uk/biostudies/studies/S-EPMC9896655biostudies-literatureUnknown15(677)Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and <i>SERT</i> promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in <i>SERT</i>^-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptoScience translational medicineDecreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.PMC9896655R01 HL131872P30 CA013696Nissim IPressly BBOyama MAFerrari GSimpson MTD'Angelo AMCamillo CBrown CKrieger AMCastillero ESalvati EAghali AKeeney SJMoreno VLevy RJGrau JBRauova LKurade MShukla HJStachelek SJFitzpatrick EInamdar VVErwin WCfalseDecreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and <i>SERT</i> promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in <i>SERT</i>^-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin recepto2023-01-01T00:00:00Z2023 Jan2025-04-04T03:01:12.478Z2025-04-04T03:01:12.478ZS-EPMC98966553659900510.1126/scitranslmed.adc9606