Key result
Tenascin C expression was significantly upregulated following ischemic mitral regurgitation and correlated strongly with increased leaflet thickness (R = 0.84, p < 0.001), promoting endothelial-to-mesenchymal transition.
Why the study?
Ischemic mitral regurgitation features adverse valvular remodeling and endothelial-to-mesenchymal transition, prompting researchers to test whether tenascin C contributes to this excess remodeling.
Effect estimate: R = 0.84
p-value: p=<0.001
Tenascin C promotes valvular remodeling and endothelial-to-mesenchymal transition in ischemic mitral regurgitation via TLR4, representing a potential therapeutic target.
Hypothesis-generating for TNC-targeted therapy in ischemic MR; prospective trials needed before clinical consideration.
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.
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Hamza et al. (2020) studied Ischemic mitral regurgitation (n=30). Ischemic mitral regurgitation vs. Healthy controls was evaluated on Correlation between Tenascin C expression and leaflet thickness (R = 0.84, p=<0.001). Tenascin C expression was significantly upregulated following ischemic mitral regurgitation and correlated strongly with increased leaflet thickness (R = 0.84, p < 0.001), promoting endothelial-to-mesenchymal transition.
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