{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:09:25Z","timestamp":1790309365107,"version":"4.1.0"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Ludwig Boltzmann Institut","award":["REM2017-20"],"award-info":[{"award-number":["REM2017-20"]}]},{"name":"Medical Scientific Fund of the Mayor of the City of Vienna","award":["AP18124BGM"],"award-info":[{"award-number":["AP18124BGM"]}]},{"DOI":"10.13039\/501100005788","name":"Medical University of Vienna","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005788","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Basic Res Cardiol"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ischemic mitral regurgitation (MR) is a frequent complication of myocardial infarction (MI) characterized by adverse remodeling both at the myocardial and valvular levels. Persistent activation of valvular endothelial cells leads to leaflet fibrosis through endothelial-to-mesenchymal transition (EMT). Tenascin C (TNC), an extracellular matrix glycoprotein involved in cardiovascular remodeling and fibrosis, was also identified in inducing epithelial-to-mesenchymal transition. In this study, we hypothesized that TNC also plays a role in the valvular remodeling observed in ischemic MR by contributing to valvular excess EMT. Moderate ischemic MR was induced by creating a posterior papillary muscle infarct (7 pigs and 7 sheep). Additional animals (7 pigs and 4 sheep) served as controls. Pigs and sheep were sacrificed after 6\u00a0weeks and 6\u00a0months, respectively. TNC expression was upregulated in the pig and sheep experiments at 6\u00a0weeks and 6\u00a0months, respectively, and correlated well with leaflet thickness (<jats:italic>R<\/jats:italic>\u2009=\u20090.68; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001 at 6\u00a0weeks, <jats:italic>R<\/jats:italic>\u2009=\u20090.84; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001 at 6\u00a0months). To confirm the translational potential of our findings, we obtained mitral valves from patients with ischemic cardiomyopathy presenting MR (<jats:italic>n<\/jats:italic>\u2009=\u20095). Indeed, TNC was also expressed in the mitral leaflets of these. Furthermore, TNC induced EMT in isolated porcine mitral valve endothelial cells (MVEC). Interestingly, Toll-like receptor 4 (TLR4) inhibition prevented TNC-mediated EMT in MVEC. We identified here for the first time a new contributor to valvular remodeling in ischemic MR, namely TNC, which induced EMT through TLR4. Our findings might set the path for novel therapeutic targets for preventing or limiting ischemic MR.<\/jats:p>","DOI":"10.1007\/s00395-020-00837-5","type":"journal-article","created":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T13:04:48Z","timestamp":1606827888000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Tenascin C promotes valvular remodeling in two large animal models of ischemic mitral regurgitation"],"prefix":"10.1007","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3025-7064","authenticated-orcid":false,"given":"Ouafa","family":"Hamza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Kiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Margarethe","family":"Kramer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Trojanek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar","family":"Abraham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eylem","family":"Acar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Nagel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena Eva","family":"Tretter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melitta","family":"Kitzw\u00f6gerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno K.","family":"Podesser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,1]]},"reference":[{"key":"837_CR1","doi-asserted-by":"publisher","first-page":"309598","DOI":"10.1161\/CIRCRESAHA.116.309598","volume":"116","author":"J Bischoff","year":"2016","unstructured":"Bischoff J, Casanovas G, Wylie-Sears J, Kim D-H, Bartko P, Guerrero J, Dal-Bianco J, Beaudoin J, Garcia M, Sullivan S, Seybolt M, Morris B, Keegan J, Irvin W, Aikawa E, Levine R (2016) CD45 expression in mitral valve endothelial cells after myocardial infarction. Circ Res 116:309598. https:\/\/doi.org\/10.1161\/CIRCRESAHA.116.309598","journal-title":"Circ Res"},{"key":"837_CR2","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1002\/(SICI)1097-0177(199901)214:1<81::AID-DVDY8>3.0.CO;2-3","volume":"214","author":"AS Boyer","year":"1999","unstructured":"Boyer AS, Erickson CP, Runyan RB (1999) Epithelial-mesenchymal transformation in the embryonic heart is mediated through distinct pertussis toxin-sensitive and TGF\u03b2 signal transduction mechanisms. Dev Dyn 214:81\u201391. https:\/\/doi.org\/10.1002\/(SICI)1097-0177(199901)214:1%3c81::AID-DVDY8%3e3.0.CO;2-3","journal-title":"Dev Dyn"},{"key":"837_CR3","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.1098\/rstb.2007.2127","volume":"362","author":"JT Butcher","year":"2007","unstructured":"Butcher JT, Nerem RM (2007) Valvular endothelial cells and the mechanoregulation of valvular pathology. Philos Trans R Soc Lond B Biol Sci 362:1445\u20131457. https:\/\/doi.org\/10.1098\/rstb.2007.2127","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"837_CR4","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.844019","author":"M Chaput","year":"2009","unstructured":"Chaput M, Handschumacher MD, Guerrero JL, Holmvang G, Dai-Bianco JP, Sullivan S, Vlahakes GJ, Hung J, Levine RA (2009) Mitral leaflet adaptation to ventricular remodeling prospective changes in a model of ischemic mitral regurgitation. Circulation. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.109.844019","journal-title":"Circulation"},{"key":"837_CR5","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1161\/CIRCRESAHA.109.201566","volume":"105","author":"MD Combs","year":"2009","unstructured":"Combs MD, Yutzey KE (2009) Heart valve development: Regulatory networks in development and disease. Circ Res 105:408\u2013421. https:\/\/doi.org\/10.1161\/CIRCRESAHA.109.201566","journal-title":"Circ Res"},{"key":"837_CR6","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1161\/CIRCULATIONAHA.108.846782","volume":"120","author":"JP Dal-Bianco","year":"2009","unstructured":"Dal-Bianco JP, Aikawa E, Bischoff J, Guerrero JL, Handschumacher MD, Sullivan S, Johnson B, Titus JS, Iwamoto Y, Wylie-Sears J, Levine RA, Carpentier A (2009) Active adaptation of the tethered mitral valve: Insights into a compensatory mechanism for functional mitral regurgitation. Circulation 120:334\u2013342. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.108.846782","journal-title":"Circulation"},{"key":"837_CR7","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.jacc.2015.10.092","volume":"67","author":"JP Dal-Bianco","year":"2016","unstructured":"Dal-Bianco JP, Aikawa E, Bischoff J, Guerrero JL, Hjortnaes J, Beaudoin J, Szymanski C, Bartko PE, Seybolt MM, Handschumacher MD, Sullivan S, Garcia ML, Mauskapf A, Titus JS, Wylie-Sears J, Irvin WS, Chaput M, Messas E, Hag\u00e8ge AA, Carpentier A, Levine RA (2016) Myocardial infarction alters adaptation of the tethered mitral valve. J Am Coll Cardiol 67:275\u2013287. https:\/\/doi.org\/10.1016\/j.jacc.2015.10.092","journal-title":"J Am Coll Cardiol"},{"issue":"6","key":"837_CR8","doi-asserted-by":"publisher","first-page":"e518","DOI":"10.4244\/EIJ-D-19-00095","volume":"16","author":"O Hamza","year":"2020","unstructured":"Hamza O, Kiss A, Kramer AM, Tillmann KE, Podesser BK (2020) A novel percutaneous closed chest swine model of ischaemic mitral regurgitation guided by contrast echocardiography. EuroIntervention 16(6):e518\u2013e522. https:\/\/doi.org\/10.4244\/EIJ-D-19-00095 (PMID: 31235459)","journal-title":"EuroIntervention"},{"key":"837_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep27051","volume":"6","author":"Y He","year":"2016","unstructured":"He Y, Ou Z, Chen X, Zu X, Liu L, Li Y, Cao Z, Chen M, Chen Z, Chen H, Qi L, Wang L (2016) LPS\/TLR4 signaling enhances TGF-\u03b2 response through downregulating BAMBI during prostatic hyperplasia. Scientific Reports 6:1\u201313. https:\/\/doi.org\/10.1038\/srep27051","journal-title":"Scientific Reports"},{"key":"837_CR10","doi-asserted-by":"publisher","first-page":"1811","DOI":"10.1167\/iovs.16-21331","volume":"58","author":"H Hernandez","year":"2017","unstructured":"Hernandez H, Medina-Ortiz WE, Luan T, Clark AF, McDowell CM (2017) Crosstalk between transforming growth factor beta-2 and toll-like receptor 4 in the trabecular meshwork. Ophthalmol Vis Sci 58:1811\u20131823. https:\/\/doi.org\/10.1167\/iovs.16-21331","journal-title":"Ophthalmol Vis Sci"},{"key":"837_CR11","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1038\/labinvest.3780313","volume":"81","author":"K Imanaka-Yoshida","year":"2001","unstructured":"Imanaka-Yoshida K, Hiroe M, Nishikawa T, Ishiyama S, Shimojo T, Ohta Y, Sakakura T, Yoshida T (2001) Tenascin-C modulates adhesion of cardiomyocytes to extracellular matrix during tissue remodeling after myocardial infarction. Lab Invest 81:1015\u20131024. https:\/\/doi.org\/10.1038\/labinvest.3780313","journal-title":"Lab Invest"},{"key":"837_CR12","doi-asserted-by":"publisher","first-page":"169","DOI":"10.3400\/avd.ra.17-00118","volume":"11","author":"K Imanaka-Yoshida","year":"2018","unstructured":"Imanaka-Yoshida K, Matsumoto K (2018) Multiple Roles of Tenascins in Homeostasis and Pathophysiology of Aorta. Ann Vasc Dis 11:169\u2013180. https:\/\/doi.org\/10.3400\/avd.ra.17-00118","journal-title":"Ann Vasc Dis"},{"key":"837_CR13","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1038\/sj.onc.1207064","volume":"23","author":"M Jinnin","year":"2004","unstructured":"Jinnin M, Ihn H, Asano Y, Yamane K, Trojanowska M, Tamaki K (2004) Tenascin-C upregulation by transforming growth factor-beta in human dermal fibroblasts involves Smad3, Sp1, and Ets1. Oncogene 23:1656\u20131667. https:\/\/doi.org\/10.1038\/sj.onc.1207064","journal-title":"Oncogene"},{"key":"837_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/oncsis.2013.27","author":"D Katoh","year":"2013","unstructured":"Katoh D, Nagaharu K, Shimojo N, Hanamura N, Yamashita M, Kozuka Y, Imanaka-Yoshida K, Yoshida T (2013) Binding of \u03b1v\u03b21 and \u03b1v\u03b26 integrins to tenascin-C induces epithelial-mesenchymal transition-like change of breast cancer cells. Oncogenesis. https:\/\/doi.org\/10.1038\/oncsis.2013.27","journal-title":"Oncogenesis"},{"key":"837_CR15","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.jacc.2018.09.089","volume":"73","author":"JC Kovacic","year":"2019","unstructured":"Kovacic JC, Dimmeler S, Harvey RP, Finkel T, Aikawa E, Krenning G, Baker AH (2019) Endothelial to mesenchymal transition in cardiovascular disease: JACC State-of-the-Art Review. J Am Coll Cardiol 73:190\u2013209. https:\/\/doi.org\/10.1016\/j.jacc.2018.09.089","journal-title":"J Am Coll Cardiol"},{"key":"837_CR16","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.jacc.2019.11.039","volume":"75","author":"O Marsit","year":"2020","unstructured":"Marsit O, Clavel MA, C\u00f4t\u00e9-Laroche C, Hadjadj S, Bouchard MA, Handschumacher MD, Clisson M, Drolet MC, Boulanger MC, Kim DH, Guerrero JL, Bartko PE, Couet J, Arsenault M, Mathieu P, Pibarot P, A\u00efkawa E, Bischoff J, Levine RA, Beaudoin J (2020) Attenuated mitral leaflet enlargement contributes to functional mitral regurgitation after myocardial infarction. J Am Coll Cardiol 75:395\u2013405. https:\/\/doi.org\/10.1016\/j.jacc.2019.11.039","journal-title":"J Am Coll Cardiol"},{"key":"837_CR17","doi-asserted-by":"publisher","DOI":"10.1369\/0022155418757443","author":"AM Marzeda","year":"2018","unstructured":"Marzeda AM, Midwood KS (2018) Internal affairs: tenascin-C as a clinically relevant, endogenous driver of innate immunity. J Histochem Cytochem. https:\/\/doi.org\/10.1369\/0022155418757443","journal-title":"J Histochem Cytochem"},{"key":"837_CR18","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1146\/annurev.iy.12.040194.005015","volume":"12","author":"P Matzinger","year":"1994","unstructured":"Matzinger P (1994) Tolerance, danger, and the extended family. Annu Rev Immunol 12:991\u20131045. https:\/\/doi.org\/10.1146\/annurev.iy.12.040194.005015","journal-title":"Annu Rev Immunol"},{"key":"837_CR19","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1007\/s11886-004-0005-z","volume":"6","author":"MR Mehra","year":"2004","unstructured":"Mehra MR, Gheorghiade M, Bonow RO (2004) Mitral regurgitation in chronic heart failure: More questions than answers? Curr Cardiol Rep 6:96\u201399. https:\/\/doi.org\/10.1007\/s11886-004-0005-z (PMID: 14759351)","journal-title":"Curr Cardiol Rep"},{"key":"837_CR20","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1038\/nm.1987","volume":"15","author":"K Midwood","year":"2009","unstructured":"Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A, Chan E, Drexler S, Sofat N, Kashiwagi M, Orend G, Brennan F, Foxwell B (2009) Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med 15:774\u2013780. https:\/\/doi.org\/10.1038\/nm.1987","journal-title":"Nat Med"},{"key":"837_CR21","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.ijcard.2019.03.003","volume":"285","author":"PM Pilz","year":"2019","unstructured":"Pilz PM, Hamza O, Gidl\u00f6f O, Gon\u00e7alves IF, Tretter EV, Trojanek S, Abraham D, Heber S, Haller PM, Podesser BK, Kiss A (2019) Remote ischemic perconditioning attenuates adverse cardiac remodeling and preserves left ventricular function in a rat model of reperfused myocardial infarction. Int J Cardiol 285:72\u201379. https:\/\/doi.org\/10.1016\/j.ijcard.2019.03.003","journal-title":"Int J Cardiol"},{"key":"837_CR22","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1097\/HJH.0000000000001628","volume":"36","author":"BK Podesser","year":"2018","unstructured":"Podesser BK, Kreibich M, Dzilic E, Santer D, F\u00f6rster L, Trojanek S, Abraham D, Kr\u0161\u0161\u00e1k M, Klein KU, Tretter EV, Kaun C, Wojta J, Kapeller B, Gon\u00e7alves IF, Trescher K, Kiss A (2018) Tenascin-C promotes chronic pressure overloadinduced cardiac dysfunction, hypertrophy and myocardial fibrosis. J Hypertens 36:847\u2013856. https:\/\/doi.org\/10.1097\/HJH.0000000000001628","journal-title":"J Hypertens"},{"key":"837_CR23","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.jmbbm.2012.07.001","volume":"15","author":"MK Rausch","year":"2012","unstructured":"Rausch MK, Tibayan FA, Craig Miller D, Kuhl E (2012) Evidence of adaptive mitral leaflet growth. J Mech Behav Biomed Mater 15:208\u2013217. https:\/\/doi.org\/10.1016\/j.jmbbm.2012.07.001","journal-title":"J Mech Behav Biomed Mater"},{"key":"837_CR24","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/S0735-1097(01)01705-3","volume":"39","author":"J Satta","year":"2002","unstructured":"Satta J, Melkko J, P\u00f6ll\u00e4nen R, Tuukkanen J, P\u00e4\u00e4kk\u00f6 P, Ohtonen P, Mennander A, Soini Y (2002) Progression of human aortic valve stenosis is associated with tenascin-C expression. J Am Coll Cardiol 39:96\u2013101. https:\/\/doi.org\/10.1016\/S0735-1097(01)01705-3","journal-title":"J Am Coll Cardiol"},{"key":"837_CR25","doi-asserted-by":"publisher","first-page":"21840","DOI":"10.1074\/jbc.274.31.21840","volume":"274","author":"K Yamamoto","year":"1999","unstructured":"Yamamoto K, Dang QN, Kennedy SP, Osathanondh R, Kelly RA, Lee RT (1999) Induction of tenascin-C in cardiac myocytes by mechanical deformation - Role of reactive oxygen species. J Biol Chem 274:21840\u201321846. https:\/\/doi.org\/10.1074\/jbc.274.31.21840","journal-title":"J Biol Chem"},{"key":"837_CR26","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.echo.2017.01.007","volume":"30","author":"WA Zoghbi","year":"2017","unstructured":"Zoghbi WA, Adams D, Bonow RO, Enriquez-Sarano M, Foster E, Grayburn PA, Hahn RT, Han Y, Hung J, Lang RM, Little SH, Shah DJ, Shernan S, Thavendiranathan P, Thomas JD, Weissman NJ (2017) Recommendations for noninvasive evaluation of native valvular regurgitation: a Report from the American Society of Echocardiography Developed in Collaboration with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr 30:303\u2013371. https:\/\/doi.org\/10.1016\/j.echo.2017.01.007","journal-title":"J Am Soc Echocardiogr"}],"container-title":["Basic Research in Cardiology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00395-020-00837-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s00395-020-00837-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00395-020-00837-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T05:45:29Z","timestamp":1610516729000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s00395-020-00837-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12]]},"references-count":26,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["837"],"URL":"https:\/\/doi.org\/10.1007\/s00395-020-00837-5","relation":{},"ISSN":["0300-8428","1435-1803"],"issn-type":[{"value":"0300-8428","type":"print"},{"value":"1435-1803","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12]]},"assertion":[{"value":"12 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 November 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 December 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors have no conflict of interest to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"76"}}