{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T22:46:49Z","timestamp":1789771609557,"version":"4.0.1"},"reference-count":40,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"677","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,1,4]]},"abstract":"<jats:p>\n            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\n            <jats:italic>SERT<\/jats:italic>\n            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\n            <jats:italic>SERT<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            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 receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or\n            <jats:italic>SERT<\/jats:italic>\n            knockdown resulted in thickened MV leaflets. Similarly, silencing of\n            <jats:italic>SERT<\/jats:italic>\n            in normal human MVICs led to up-regulation of transforming growth factor \u03b21 (\n            <jats:italic>TGF<\/jats:italic>\n            \u03b2\n            <jats:italic>1<\/jats:italic>\n            ) and collagen (\n            <jats:italic>COL1A1<\/jats:italic>\n            ) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased\n            <jats:italic>SERT<\/jats:italic>\n            expression and increased\n            <jats:italic>HTR2B<\/jats:italic>\n            expression. Fluoxetine treatment and LL genotype were also associated with increased\n            <jats:italic>COL1A1<\/jats:italic>\n            expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adc9606","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T18:58:14Z","timestamp":1672858694000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":18,"title":["Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2213-5809","authenticated-orcid":true,"given":"Estibaliz","family":"Castillero","sequence":"first","affiliation":[{"name":"Department of Surgery, Columbia University, New\u00a0York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7655-7890","authenticated-orcid":true,"given":"Emmett","family":"Fitzpatrick","sequence":"additional","affiliation":[{"name":"Pediatric Heart Valve Center and the Division of Cardiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9605-8140","authenticated-orcid":true,"given":"Samuel J.","family":"Keeney","sequence":"additional","affiliation":[{"name":"Pediatric Heart Valve Center and the Division of Cardiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex M.","family":"D\u2019Angelo","sequence":"additional","affiliation":[{"name":"Department of Surgery, Columbia University, New\u00a0York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin B.","family":"Pressly","sequence":"additional","affiliation":[{"name":"Pediatric Heart Valve Center and the Division of Cardiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Surgery, Columbia University, New\u00a0York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9664-6655","authenticated-orcid":true,"given":"Mangesh","family":"Kurade","sequence":"additional","affiliation":[{"name":"Department of Surgery, Columbia University, New\u00a0York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Clinton","family":"Erwin","sequence":"additional","affiliation":[{"name":"Department of Surgery, Columbia University, New\u00a0York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0855-066X","authenticated-orcid":true,"given":"Vivian","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Surgery, Columbia University, New\u00a0York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8000-3188","authenticated-orcid":true,"given":"Chiara","family":"Camillo","sequence":"additional","affiliation":[{"name":"Department of Surgery, Columbia University, New\u00a0York, NY 10032, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halley J.","family":"Shukla","sequence":"additional","affiliation":[{"name":"Pediatric Heart Valve Center and the Division of Cardiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishali V.","family":"Inamdar","sequence":"additional","affiliation":[{"name":"Pediatric Heart Valve Center and the Division of Cardiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1056-4139","authenticated-orcid":true,"given":"Arbi","family":"Aghali","sequence":"additional","affiliation":[{"name":"Pediatric Heart Valve Center and the Division of Cardiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan B.","family":"Grau","sequence":"additional","affiliation":[{"name":"Valley Hospital Heart Institute, Ridgewood, NJ 07450, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Salvati","sequence":"additional","affiliation":[{"name":"Pediatric Heart Valve Center and the Division of Cardiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itzhak","family":"Nissim","sequence":"additional","affiliation":[{"name":"Division of Human Genetics and Metabolic Disease, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Department of Pediatrics, Biochemistry, and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1990-3077","authenticated-orcid":true,"given":"Lubica","family":"Rauova","sequence":"additional","affiliation":[{"name":"Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5218-9226","authenticated-orcid":true,"given":"Mark A.","family":"Oyama","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9233-1752","authenticated-orcid":true,"given":"Stanley J.","family":"Stachelek","sequence":"additional","affiliation":[{"name":"Pediatric Heart Valve Center and the Division of Cardiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chase","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4296-1278","authenticated-orcid":true,"given":"Abba M.","family":"Krieger","sequence":"additional","affiliation":[{"name":"Statistics Department, Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Levy","sequence":"additional","affiliation":[{"name":"Pediatric Heart Valve Center and the Division of Cardiology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8863-2496","authenticated-orcid":true,"given":"Giovanni","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Department of Surgery, Columbia University, New\u00a0York, NY 10032, USA."},{"name":"Department of Biomedical Engineering, Columbia University, New\u00a0York, NY 10027, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69208-8"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.553750"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199708283370901"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.5858\/2001-125-1555-AAMFPV"},{"key":"e_1_3_3_6_2","first-page":"44","article-title":"Autocrine serotonin and transforming growth factor beta 1 signaling mediates spontaneous myxomatous mitral valve disease","volume":"18","author":"Disatian S.","year":"2009","unstructured":"S.\u00a0Disatian, E. 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H.","year":"2019","unstructured":"J. H.\u00a0Fortier, B.\u00a0Pizzarotti, R. E.\u00a0Shaw, R. J.\u00a0Levy, G.\u00a0Ferrari, J.\u00a0Grau, Drug-associated valvular heart diseases and serotonin-related pathways: A meta-analysis. Heart 105, 1140\u20131148 (2019).","journal-title":"Heart"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/icvts\/ivab090"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.051517"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.3390\/ph14121268"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2015.335"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adc9606","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T17:43:07Z","timestamp":1705426987000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adc9606"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,4]]},"references-count":40,"journal-issue":{"issue":"677","published-print":{"date-parts":[[2023,1,4]]}},"alternative-id":["10.1126\/scitranslmed.adc9606"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adc9606","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,4]]},"assertion":[{"value":"2022-05-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadc9606"}}