PMID- 33258993 OWN - NLM STAT- MEDLINE DCOM- 20211018 LR - 20211018 IS - 1435-1803 (Electronic) IS - 0300-8428 (Print) IS - 0300-8428 (Linking) VI - 115 IP - 6 DP - 2020 Dec 1 TI - Tenascin C promotes valvular remodeling in two large animal models of ischemic mitral regurgitation. PG - 76 LID - 10.1007/s00395-020-00837-5 [doi] LID - 76 AB - 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 weeks and 6 months, respectively. TNC expression was upregulated in the pig and sheep experiments at 6 weeks and 6 months, respectively, and correlated well with leaflet thickness (R = 0.68; p < 0.001 at 6 weeks, R = 0.84; p < 0.001 at 6 months). To confirm the translational potential of our findings, we obtained mitral valves from patients with ischemic cardiomyopathy presenting MR (n = 5). 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. FAU - Hamza, Ouafa AU - Hamza O AUID- ORCID: 0000-0002-3025-7064 AD - Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. FAU - Kiss, Attila AU - Kiss A AD - Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. FAU - Kramer, Anne-Margarethe AU - Kramer AM AD - Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. FAU - Trojanek, Sandra AU - Trojanek S AD - Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria. FAU - Abraham, Dietmar AU - Abraham D AD - Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria. FAU - Acar, Eylem AU - Acar E AD - Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. FAU - Nagel, Felix AU - Nagel F AD - Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. AD - Department of Cardiac Surgery, Karl Landsteiner University, St. Polten, Austria. FAU - Tretter, Verena Eva AU - Tretter VE AD - Department of Anesthesia, General Intensive Care and Pain Therapy, Medical University of Vienna, Vienna, Austria. FAU - Kitzwogerer, Melitta AU - Kitzwogerer M AD - Department of Pathology, Karl Landsteiner University, St. Polten, Austria. FAU - Podesser, Bruno K AU - Podesser BK AD - Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. bruno.podesser@meduniwien.ac.at. AD - Department of Cardiac Surgery, Karl Landsteiner University, St. Polten, Austria. bruno.podesser@meduniwien.ac.at. LA - eng GR - REM2017-20/Ludwig Boltzmann Institut/International GR - AP18124BGM/Medical Scientific Fund of the Mayor of the City of Vienna/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201201 PL - Germany TA - Basic Res Cardiol JT - Basic research in cardiology JID - 0360342 RN - 0 (TNC protein, human) RN - 0 (Tenascin) RN - 0 (Toll-Like Receptor 4) SB - IM MH - Aged MH - Aged, 80 and over MH - Animals MH - Cells, Cultured MH - Disease Models, Animal MH - Endothelial Cells/*metabolism/pathology MH - *Epithelial-Mesenchymal Transition MH - Female MH - Humans MH - Male MH - Middle Aged MH - Mitral Valve/*metabolism/pathology/physiopathology MH - Mitral Valve Insufficiency/etiology/*metabolism/pathology/physiopathology MH - Myocardial Infarction/*complications MH - Sheep, Domestic MH - Signal Transduction MH - Sus scrofa MH - Tenascin/*metabolism MH - Toll-Like Receptor 4/metabolism MH - Up-Regulation PMC - PMC7716900 OTO - NOTNLM OT - Endothelial-to-mesenchymal transition OT - Ischemic mitral regurgitation OT - Leaflet remodeling OT - Myocardial infarction OT - Tenascin C COIS- The authors have no conflict of interest to declare. EDAT- 2020/12/02 06:00 MHDA- 2021/10/21 06:00 PMCR- 2020/12/01 CRDT- 2020/12/01 12:44 PHST- 2020/10/12 00:00 [received] PHST- 2020/11/25 00:00 [accepted] PHST- 2020/12/01 12:44 [entrez] PHST- 2020/12/02 06:00 [pubmed] PHST- 2021/10/21 06:00 [medline] PHST- 2020/12/01 00:00 [pmc-release] AID - 10.1007/s00395-020-00837-5 [pii] AID - 837 [pii] AID - 10.1007/s00395-020-00837-5 [doi] PST - epublish SO - Basic Res Cardiol. 2020 Dec 1;115(6):76. doi: 10.1007/s00395-020-00837-5.