E3泛素连接酶WWP1对TGF-β介导的心肌纤维化的作用及其机制研究

Cardiac fibrosis is a key event in the progression of diverse cardiac diseases that leads to heart failure. TGF-β has been reported to be a key mediator of cardiac fibriosis. WWP1, an E3 ubiquitin ligase, has been reported to play an important role in negatively regulating TGF-β signaling pathways by polyubiquitination of several key moleculars. However, whether WWP1 can regulate the progression of cardiac fibrosis has not been reported. Our previous results shown that WWP1 was decreased in vivo in pressure overloaded rat hearts and in cultured neonatal rat cardiac fibroblasts (NRCFs) exposed to TGF-β (10ng/mL) in vitro. In addition, transfection of adv-WWP1 significantly attenuated TGF-β induced differentiation in cardiac fibroblast. These findings indicate an association between WWP1 and cardiac fibrotic response, suggesting a potent role of WWP1 in cardiac fibroblast activation and cardiac fibrosis. To probe this hypothesis, we will examine the effect of WWP1 on cardiac fibrosis induced by pressure overload and TGF-β induced of activation cardiac fibroblasts and further to explore what the mechanisms is, which may provides a novel target for treatment of cardiac fibrosis.

心肌纤维化是多种心脏疾病发展至心力衰竭的重要原因。研究显示，TGF-β信号对心肌纤维化具有重要调控意义。WWP1是一种E3泛素连接酶，其可通过泛素化修饰TGF-β信号中关键分子，负性调控TGF-β及其下游信号转导。但WWP1是否调控心肌纤维化的发展尚不清楚。我们前期发现：压力过负荷诱导的纤维化心肌组织及TGF-β（10ng/mL）刺激的心肌成纤维细胞中WWP1表达均显著降低，而过表达WWP1能明显抑制TGF-β诱导的心肌成纤维细胞分化。提示WWP1可能是调控心肌成纤维细胞活化及心肌纤维化的关健分子。本项目拟在前期研究基础上分别以主动脉弓缩窄术在体复制大鼠心肌纤维化及TGF-β诱导体外心肌成纤维细胞活化为模型，探讨WWP1是否为调控TGF-β介导心肌纤维化的关键分子，以及WWP1调控TGF-β介导心肌纤维化的分子机制，该研究有望为防治心肌纤维化提供新的靶点。

心肌纤维化是多种心脏疾病发展至心力衰竭的重要原因。研究显示，TGF-β信号对心肌纤维化具有重要调控意义。WWP1是一种E3泛素连接酶，其可通过泛素化修饰TGF-β信号中关键分子，负性调控TGF-β及其下游信号转导。但WWP1是否调控心肌纤维化的发展尚不清楚。我们的研究发现，压力过负荷诱导的纤维化心肌组织及TGF-β（10ng/mL）刺激的心肌成纤维细胞中WWP1表达均显著降低。使用AAV9过表达心肌组织中的WWP1可显著改善压力过负荷诱导的小鼠心肌肥大、心肌纤维化以及心功能失常。此外，使用腺病毒过表达原代心肌成纤维细胞中的WWP1可显著抑制TGF-β诱导的心肌成纤维细胞增殖、分化以及胶原合成增加。过表达WWP1可抑制TGF-β所致的心肌成纤维细胞中MAPK（p38/ERK/JNK）信号通路的激活。本研究首次揭示了WWP1在心肌纤维化中的作用，有望为心肌纤维化及压力过负荷所致心衰的治疗提供新的思路与靶点。