{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:08:24Z","timestamp":1790755704868,"version":"4.1.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,4,15]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Aortic stenosis due to deleterious remodeling of the aortic valve is a health concern since it can be corrected only by valve replacement due to the poor knowledge of cellular mechanisms involved. Fibroblastic valvular interstitial cells (VICs) play a central role in valve leaflet stiffness by trans\u2010differentiation into osteoblast\u2010like cells leading to calcification. The TRPM4 (transient receptor potential melastatin 4) cation channel was shown to participate in cardiac fibroblast remodeling. It is also involved in radiation\u2010induced aortic valve remodeling in\u00a0vivo in mice. We hypothesized that TRPM4 might participate in human VIC transition to osteoblastic phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">Human aortic valves were collected from patients undergoing surgical valve replacement. Isolated VICs were maintained 14\u2009days in culture in standard or pro\u2010calcifying media and submitted to the TRPM4 inhibitor 9\u2010phenanthrol, or small hairpin RNA\u2013TRPM4. Osteogenic differentiation was evaluated by measuring hydroxyapatite crystals by Alizarin red staining and protein expression of osteogenic markers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Western blot on VICs revealed TRPM4 protein expression and channel functionality was confirmed by patch\u2010clamp recordings exhibiting a cationic current sensitive to voltage and internal Ca\n                      <jats:sup>2+<\/jats:sup>\n                      . VICs maintained in pro\u2010calcifying media exhibited a higher mineralization than in standard media, with an increase in osteogenic markers. Mineralization and osteogenic markers (bone morphogenetic protein 2, runt\u2010related transcription factor 2) were decreased when pro\u2010calcifying media contained 9\u2010phenanthrol or small hairpin RNA\u2013TRPM4. Similarly, SMAD1\/5 and nuclear factor of activated T\u2010cell pathways were stimulated in pro\u2010calcifying media conditions compared with standard media but reduced by 9\u2010phenanthrol or small hairpin RNA\u2013TRPM4.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">TRPM4 participates in osteogenic differentiation of human VICs and thus appears as a target to prevent aortic valve remodeling.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.038542","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T23:13:50Z","timestamp":1744067630000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Contribution of the TRPM4 Channel to Osteogenic Differentiation of Human Aortic Valve Interstitial Cells"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5868-474X","authenticated-orcid":false,"given":"Margaux","family":"Aize","sequence":"first","affiliation":[{"name":"Normandy University, UNICAEN, UR4650, Physiopathologie et Strat\u00e9gies d\u2019Imagerie du Remodelage cardiovasculaire (PSIR)","place":["Caen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9094-863X","authenticated-orcid":false,"given":"Arthur","family":"Boil\u00e8ve","sequence":"additional","affiliation":[{"name":"Normandy University, UNICAEN, UR4650, Physiopathologie et Strat\u00e9gies d\u2019Imagerie du Remodelage cardiovasculaire (PSIR)","place":["Caen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0575-8112","authenticated-orcid":false,"given":"Benoit D.","family":"Roussel","sequence":"additional","affiliation":[{"name":"Normandy University, UNICAEN, INSERM","place":["Caen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Brard","sequence":"additional","affiliation":[{"name":"Normandy University, UNICAEN, UR4650, Physiopathologie et Strat\u00e9gies d\u2019Imagerie du Remodelage cardiovasculaire (PSIR)","place":["Caen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harlyne","family":"Mpweme Bangando","sequence":"additional","affiliation":[{"name":"Normandy University, UNICAEN, UR4650, Physiopathologie et Strat\u00e9gies d\u2019Imagerie du Remodelage cardiovasculaire (PSIR)","place":["Caen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corentin","family":"Kerevel","sequence":"additional","affiliation":[{"name":"Normandy University, UNICAEN, UR4650, Physiopathologie et Strat\u00e9gies d\u2019Imagerie du Remodelage cardiovasculaire (PSIR)","place":["Caen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6014-6912","authenticated-orcid":false,"given":"Alexandre","family":"Lebrun","sequence":"additional","affiliation":[{"name":"Normandy University, UNICAEN, UR4650, Physiopathologie et Strat\u00e9gies d\u2019Imagerie du Remodelage cardiovasculaire (PSIR)","place":["Caen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hind","family":"Messaoudi","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie, INSERM, ENVI UMR1096","place":["Rouen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Saplacan","sequence":"additional","affiliation":[{"name":"CHU de Caen Normandie","place":["Caen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1578-0922","authenticated-orcid":false,"given":"Alain","family":"Manrique","sequence":"additional","affiliation":[{"name":"Normandy University, UNICAEN, UR4650, Physiopathologie et Strat\u00e9gies d\u2019Imagerie du Remodelage cardiovasculaire (PSIR)","place":["Caen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0276-8884","authenticated-orcid":false,"given":"Romain","family":"Guinamard","sequence":"additional","affiliation":[{"name":"Normandy University, UNICAEN, UR4650, Physiopathologie et Strat\u00e9gies d\u2019Imagerie du Remodelage cardiovasculaire (PSIR)","place":["Caen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6286-5013","authenticated-orcid":false,"given":"Christophe","family":"Simard","sequence":"additional","affiliation":[{"name":"Normandy University, UNICAEN, UR4650, Physiopathologie et Strat\u00e9gies d\u2019Imagerie du Remodelage cardiovasculaire (PSIR)","place":["Caen, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the STOP\u2010AS Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.041080"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69208-8"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.15420\/ecr.2015.10.2.108"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.006339"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-023-00845-7"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.02.093"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0020969"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.8.1745"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2009.06.024"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/mabi.202000268"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13122"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab757"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24065860"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00719-5"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14184477"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-020-02476-0"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0240532"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.18632\/aging.202942"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25624"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2023.1138306"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e31871"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202101863R"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.115.001145"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.155569"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208277200"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.11.023"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjp.2008.38"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-54215-2_18"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.063974"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-021-02525-2"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.206771"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr135"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1098845"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102969"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab273"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.01.016"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1098228"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12582"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108714"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031465"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.712354"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.428219"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-023-01389-x"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1136\/svn-2023-002892"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.3390\/ph15010040"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-44726-0"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.124.038542","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T11:53:22Z","timestamp":1783943602000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.124.038542"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,15]]},"references-count":46,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,4,15]]}},"alternative-id":["10.1161\/JAHA.124.038542"],"URL":"https:\/\/doi.org\/10.1161\/jaha.124.038542","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,15]]},"assertion":[{"value":"2024-08-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e038542"}}