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.

缺血性二尖瓣关闭不全 (MR) 是心肌梗塞 (MI) 的常见并发症，其特征在于心肌和瓣膜水平的不良重构。瓣膜内皮细胞的持续激活通过内皮间质转化 (EMT) 导致小叶纤维化。Tenascin C (TNC) 是一种参与心血管重塑和纤维化的细胞外基质糖蛋白，也被鉴定为诱导上皮-间质转化。在这项研究中，我们假设 TNC 也在缺血性 MR 中观察到的瓣膜重塑中起作用，因为它有助于瓣膜过度 EMT。通过产生后乳头肌梗塞（7 只猪和 7 只羊）诱导中度缺血性 MR。额外的动物（7 头猪和 4 只羊）作为对照。6周和6个月后处死猪和羊，分别。TNC 表达在猪和绵羊实验中分别在 6 周和 6 个月时上调，并且与小叶厚度相关。R  = 0.68； 在第 6 周时p < 0.001，R  = 0.84；p  < 0.001 在 6 个月）。为了证实我们的研究结果的转化潜力，我们从呈现 MR 的缺血性心肌病患者（n  = 5）中获取了二尖瓣。事实上，TNC 也在这些二尖瓣小叶中表达。此外，TNC 在分离的猪二尖瓣内皮细胞 (MVEC) 中诱导 EMT。有趣的是，Toll 样受体 4 (TLR4) 抑制阻止了 MVEC 中 TNC 介导的 EMT。我们在这里首次确定了缺血性 MR 中瓣膜重塑的新贡献者，即 TNC，它通过 TLR4 诱导 EMT。我们的发现可能为预防或限制缺血性 MR 的新治疗靶点开辟道路。