REDD1促进自噬改善内皮间充质转化对心肌纤维化的调控作用及机制研究

Cardiac fibrosis plays a crucial role in the pathogenesis of heart failure. Endothelial to mesenchymal transition (EndMT), usually characterized by loss of endothelial and gain of mesenchymal cell markers, contributes to the progression of cardiac fibrosis and inhibition of EndMT significantly attenuates cardiac fibrosis. REDD1, a stress-responsive protein, was demonstrated to inhibit cardiac hypertrophy via enhancing autophagy. However, the effects of REDD1 on cardiac fibrosis remain unknown. Our preliminary data showed that REDD1 attenuated cardiac fibroblasts proliferation and EndMT induced by transforming growth factor β (TGF-β) and also enhanced autophagy, suggesting that REDD1 may play an important role in the regulation of cardiac fibrosis. Thus, in this present study, with cardiac conditional REDD1 transgenic mice, we aim to examine the effects of REDD1 on cardiac fibrosis in a pressure overload induced heart failure model as well as an EndMT model induced by TGF-β in human coronary artery endothelial cells. Furthermore, we explore whether REDD1 regulates cardiac fibrosis via attenuating EndMT and demonstrate the precise role of autophagy in EndMT and cardiac fibrosis. Our study may provide potential therapeutic targets and theoretical basis for cardiac fibrosis and heart failure.

心肌纤维化是心力衰竭的病理基础，内皮细胞间充质转化（EndMT）是诱导心肌纤维化的重要机制，抑制EndMT可明显改善心肌纤维化。REDD1是一种应激反应蛋白，我们前期研究结果表明REDD1可激活自噬从而发挥抗心肌肥厚作用，然而目前尚无REDD1与心肌纤维化关系的研究。预实验结果表明过表达REDD1可抑制心肌成纤维细胞增殖及内皮细胞EndMT并激活自噬，提示REDD1可能对心肌纤维化具有重要调控作用。因此，本研究利用心脏条件性REDD1转基因小鼠、腺病毒转染及基因沉默技术，通过压力过负荷诱导的心力衰竭模型和TGF-β诱导的冠脉内皮细胞EndMT模型，从功能获得和缺失实验两方面评价REDD1对心肌纤维化的调控作用，深入研究REDD1是否通过抑制EndMT以调控心肌纤维化，并阐明自噬是否为REDD1调控EndMT和心肌纤维化的核心机制，旨在为心肌纤维化与心力衰竭的临床治疗提供新的靶点和理论依据。

心肌纤维化是心力衰竭的病理基础，内皮细胞间充质转化（EndMT）是诱导心肌纤维化的重要机制，抑制EndMT可明显改善心肌纤维化。REDD1是一种应激反应蛋白，我们前期研究结果表明REDD1可激活自噬从而发挥抗心肌肥厚作用，然而目前尚无REDD1与心肌纤维化关系的研究。本研究在体内实验中使用压力过负荷诱导的心肌纤维化和心力衰竭模型，在体外实验中使用TGFβ1诱导的心肌成纤维化细胞增殖模型和TGFβ2诱导的冠脉内皮细胞EndMT模型，通过成功构建心脏条件性REDD1转基因小鼠，以及使用小干扰RNA技术，从动物和细胞水平深入研究REDD1对心肌纤维化和心力衰竭的调控作用。研究发现REDD1可显著促进心肌纤维化和心力衰竭；深入研究机制发现，REDD1可能通过诱导EndMT从而促进心肌纤维化。因此，本研究阐明了REDD1对心肌纤维化和心力衰竭发生发展的影响及机制，为心肌纤维化及心力衰竭的早期干预与治疗提供理论依据和治疗靶点。