HGF下调ILK表达抑制血管内皮细胞EndMT抗心肌纤维化作用的机制研究

An underlying morphological correlate of diastolic dysfunction is cardiac fibrosis, which leads to increased stiffness of the heart. The accumulation of myofibroblasts is responsible for the development and progression of pathological fibrosis. Recently, endothelial to mesenchymal transition (EndMT), a newly recognized type of cellular transdifferentiation, has emerged as a major source of tissue myofibroblasts. In a recent work we demonstrated that HGF significantly alleviated fibrosis in a porcine MI models. In addition, we found that HGF significantly inhibited the expression of ILK, which reportedly plays a key role in the regulation of EndMT in a variety types of cells. These data suggest that HGF might regulate EndMT of cardiac endothelial cells through the ILK-mediated signal pathway. However, the mechanisms that underlie HGF regulation of ILK expression and EndMT warrant further investigation. In this project, we propose to evaluate the role of HGF/ILK pathways in the EndMT by multiple approaches including bioinformatic analysis, luciferase reporter assay, RNA interference, ChIP. Conceivably, elucidation of the molecular pathways involved in the regulation of EndMT in the pathogenesis of cardiac fibrosis may reveal novel therapeutic targets for fibrotic disorders.

心肌纤维化是心肌损伤后向心衰发展进程中的关键步骤。既往研究证实间质细胞尤其是肌纤维母细胞在此过程中起着主导作用。新近的研究表明，有相当数量的肌纤维母细胞是由血管内皮细胞通过内皮-间质转化（EndMT）而成。因而，研究EndMT的调控机制并据此制定出相应的对策将有助于临床抗心肌纤维化的疗效。我们在前期的研究中发现，肝细胞生长因子（HGF）能通过下调整合素连接激酶（ILK）的表达抑制EndMT的发生。本项目拟采用生物信息学分析、荧光素酶报告基因、RNA干扰、免疫共沉淀等方法对其机制作进一步的研究探讨；此外，我们还将通过相关的细胞学实验及动物模型等评价HGF/ILK通路中的关键基因在抑制内皮细胞EndMT发生过程中的潜在应用价值。文献检索显示，上述研究内容国内外未见报道。如获成功，不仅有助于更好地阐释HGF抗心肌纤维化的作用机制，而且有望为今后开展抗心肌纤维化治疗研究提供新的靶点。