Tenascin-C accelerates adverse ventricular remodelling after myocardial infarction by modulating macrophage polarization

AIMS Tenascin-C (TN-C) is an extracellular matrix protein undetected in the normal adult heart, but expressed in several heart diseases associated with inflammation. We previously reported that serum TN-C levels of myocardial infarction (MI) patients were elevated during the acute stage, and that patients with high peak TN-C levels were at high risk of left ventricular (LV) remodelling and poor outcome, suggesting that TN-C could play a significant role in the progression of ventricular remodelling. However, the detailed molecular mechanisms associated with this process remain unknown. We aimed to elucidate the role and underlying mechanisms associated with TN-C in adverse remodelling after MI. METHODS AND RESULTS MI was induced by permanent ligation of the coronary artery of TN-C knockout (TN-C-KO) and wild type (WT) mice. In WT mice, TN-C was expressed at the borders between intact and necrotic areas, with a peak at 3 days post-MI and observed in the immediate vicinity of infiltrating macrophages. TN-C-KO mice were protected from ventricular adverse remodelling as evidenced by a higher LV ejection fraction as compared with WT mice (19.0 ± 6.3% vs. 10.6 ± 4.4%; P < 0.001) at 3 months post-MI. During the acute phase, flow-cytometric analyses showed a decrease in F4/80+CD206lowCD45+ M1 macrophages and an increase in F4/80+CD206highCD45+ M2 macrophages in the TN-C-KO heart. To clarify the role of TN-C on macrophage polarization, we examined the direct effect of TN-C on bone marrow-derived macrophages in culture, observing that TN-C promoted macrophage shifting into an M1 phenotype via Toll-like receptor 4 (TLR4). Under M2-skewing conditions, TN-C suppressed the expression of interferon regulatory factor 4, a key transcription factor that controls M2-macrophage polarization, via TLR4, thereby inhibiting M2 polarization. CONCLUSION These results suggested that TN-C accelerates LV remodelling after MI, at least in part, by modulating M1/M2-macrophage polarization.

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