Tenascin C promotes valvular remodeling in two large animal models of ischemic mitral regurgitation

Ouafa Hamza, Attila Kiss, Anne-Margarethe Kramer, Sandra Trojanek, Dietmar Abraham, Eylem Acar, Felix Nagel, Verena Eva Tretter, Melitta Kitzwögerer, Bruno K Podesser

Research output: Journal article (peer-reviewed)Journal article

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number76
Pages (from-to)76
JournalBasic Research in Cardiology
Volume115
Issue number6
DOIs
Publication statusPublished - 1 Dec 2020

Keywords

  • Aged
  • Aged, 80 and over
  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells/metabolism
  • Epithelial-Mesenchymal Transition
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mitral Valve/metabolism
  • Mitral Valve Insufficiency/etiology
  • Myocardial Infarction/complications
  • Sheep, Domestic
  • Signal Transduction
  • Sus scrofa
  • Tenascin/metabolism
  • Toll-Like Receptor 4/metabolism
  • Up-Regulation

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