{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T12:23:37Z","timestamp":1792844617191,"version":"4.5.0"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11_suppl_1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2012,9,11]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>Little is known about the pathophysiology of myxomatous degeneration of the mitral valve, the pathological hallmark of mitral valve prolapse, associated with symptomatic mitral regurgitation, heart failure, and death. Excess transforming growth factor (TGF)-\u03b2 signaling is known to cause mitral valve degeneration and regurgitation in a mouse model of Marfan syndrome. We examined if TGF-\u03b2 signaling is dysregulated in clinical specimens of sporadic mitral valve prolapse compared with explanted nondiseased mitral valves and we tested the effects of angiotensin II receptor blockers on TGF-\u03b2 signaling in cultured human mitral valve cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>Operative specimens, cultured valve tissues, and cultured valvular interstitial cells were obtained from patients with mitral valve prolapse undergoing mitral valve repair or from organ donors without mitral valve disease. Increased extracellular matrix in diseased valve tissue correlated with an upregulation of TGF-\u03b2 expression and signaling as evidenced by SMAD2\/3 phosphorylation. Both TGF-\u03b2 ligand and signaling mediators colocalized primarily to valvular interstitial cells suggesting autocrine\/paracrine activation. In cultured valve tissue, exogenous TGF-\u03b2 increased basal extracellular matrix production, whereas serological neutralization of TGF-\u03b2 inhibited disease-driven extracellular matrix overproduction. TGF-\u03b2-induced extracellular matrix production in cultured valvular interstitial cells was dependent on SMAD2\/3 and p38 signaling and was inhibited by angiotensin II receptor blockers.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>TGF-\u03b2 has a profibrotic role in the pathogenesis of sporadic mitral valve prolapse. Attenuation of TGF-\u03b2 signaling by angiotensin II receptor blockers may represent a mechanistically based strategy to modulate the pathological progression of mitral valve prolapse in patients.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.111.082610","type":"journal-article","created":{"date-parts":[[2012,9,10]],"date-time":"2012-09-10T20:34:09Z","timestamp":1347309249000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":91,"title":["Modulation of Transforming Growth Factor-\u03b2 Signaling and Extracellular Matrix Production in Myxomatous Mitral Valves by Angiotensin II Receptor Blockers"],"prefix":"10.1161","volume":"126","author":[{"given":"Arnar","family":"Geirsson","sequence":"first","affiliation":[{"name":"From the Department of Surgery (A.G., M.S., R.A., W.L., S.H., G.T.) and the Interdepartmental Program in Vascular Biology and Therapeutics (A.G., M.S., R.A., W.L., G.T.), Yale University School of Medicine, New Haven, CT; the Veterans Affairs Connecticut Healthcare System, West Haven, CT (A.G., G.T.); and the Department of Surgery, St Mary's Hospital, Waterbury, CT (H.A., J.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansher","family":"Singh","sequence":"additional","affiliation":[{"name":"From the Department of Surgery (A.G., M.S., R.A., W.L., S.H., G.T.) and the Interdepartmental Program in Vascular Biology and Therapeutics (A.G., M.S., R.A., W.L., G.T.), Yale University School of Medicine, New Haven, CT; the Veterans Affairs Connecticut Healthcare System, West Haven, CT (A.G., G.T.); and the Department of Surgery, St Mary's Hospital, Waterbury, CT (H.A., J.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahmat","family":"Ali","sequence":"additional","affiliation":[{"name":"From the Department of Surgery (A.G., M.S., R.A., W.L., S.H., G.T.) and the Interdepartmental Program in Vascular Biology and Therapeutics (A.G., M.S., R.A., W.L., G.T.), Yale University School of Medicine, New Haven, CT; the Veterans Affairs Connecticut Healthcare System, West Haven, CT (A.G., G.T.); and the Department of Surgery, St Mary's Hospital, Waterbury, CT (H.A., J.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussain","family":"Abbas","sequence":"additional","affiliation":[{"name":"From the Department of Surgery (A.G., M.S., R.A., W.L., S.H., G.T.) and the Interdepartmental Program in Vascular Biology and Therapeutics (A.G., M.S., R.A., W.L., G.T.), Yale University School of Medicine, New Haven, CT; the Veterans Affairs Connecticut Healthcare System, West Haven, CT (A.G., G.T.); and the Department of Surgery, St Mary's Hospital, Waterbury, CT (H.A., J.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"From the Department of Surgery (A.G., M.S., R.A., W.L., S.H., G.T.) and the Interdepartmental Program in Vascular Biology and Therapeutics (A.G., M.S., R.A., W.L., G.T.), Yale University School of Medicine, New Haven, CT; the Veterans Affairs Connecticut Healthcare System, West Haven, CT (A.G., G.T.); and the Department of Surgery, St Mary's Hospital, Waterbury, CT (H.A., J.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan A.","family":"Sanchez","sequence":"additional","affiliation":[{"name":"From the Department of Surgery (A.G., M.S., R.A., W.L., S.H., G.T.) and the Interdepartmental Program in Vascular Biology and Therapeutics (A.G., M.S., R.A., W.L., G.T.), Yale University School of Medicine, New Haven, CT; the Veterans Affairs Connecticut Healthcare System, West Haven, CT (A.G., G.T.); and the Department of Surgery, St Mary's Hospital, Waterbury, CT (H.A., J.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabet","family":"Hashim","sequence":"additional","affiliation":[{"name":"From the Department of Surgery (A.G., M.S., R.A., W.L., S.H., G.T.) and the Interdepartmental Program in Vascular Biology and Therapeutics (A.G., M.S., R.A., W.L., G.T.), Yale University School of Medicine, New Haven, CT; the Veterans Affairs Connecticut Healthcare System, West Haven, CT (A.G., G.T.); and the Department of Surgery, St Mary's Hospital, Waterbury, CT (H.A., J.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Tellides","sequence":"additional","affiliation":[{"name":"From the Department of Surgery (A.G., M.S., R.A., W.L., S.H., G.T.) and the Interdepartmental Program in Vascular Biology and Therapeutics (A.G., M.S., R.A., W.L., G.T.), Yale University School of Medicine, New Haven, CT; the Veterans Affairs Connecticut Healthcare System, West Haven, CT (A.G., G.T.); and the Department of Surgery, St Mary's Hospital, Waterbury, CT (H.A., J.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199907013410101"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.carpath.2008.05.001"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/hc4601.099489"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.66.2.288"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(99)80718-8"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(99)00313-7"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008422200"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.622621"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/352337a0"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1116"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-4975(98)00314-2"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200422715"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000136520.07995.aa"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.080365"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2011.03676.x"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.01.020"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0904121"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3487831"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M100754200"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.070251"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1192149"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00099.2007"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0706585"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(94)90061-2"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124287"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1192152"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.111.082610","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T06:44:13Z","timestamp":1715582653000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.111.082610"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,9,11]]},"references-count":26,"journal-issue":{"issue":"11_suppl_1","published-print":{"date-parts":[[2012,9,11]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.111.082610"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.111.082610","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,9,11]]},"assertion":[{"value":"2012-09-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}