外泌体介导环状RNA调控miR-378促进心肌细胞自噬的作用和机制

Autophagy plays an important role in heart failure. CircRNAs affected heart failure by inhibiting miRNA activity. However, it remains to be elusive whether exosomal circRNAs affects cardiomyocyte autophagy by inhibiting miRNA activity. Our research group found that miR-378 could decrease mechanical stress-induced cardiomyocyte autophagy. We also revealed that mechanical stress increased the paracrine of exosomal circSLC8A1 in cardiac fibroblasts (CFs), which caused a significant increase in cardiomyocyte autophagy. To test whether circSLC8A1 can be bounded by miR-378, we compared the sequence of circSLC8A1 with that of miR-378 using the bioinformatics program and noticed that circSLC8A1 contains target sites of miR-378. Therefore, we propose that exosomal circSLC8A1 might increase cardiomyocyte autophagy by inhibiting miR-378. This study is designed to construct pressure overload model in vivo and in vitro, and we will examine the role of exosomal circSLC8A1 and miR-378 in the influence cardiomyocyte autophagy. In parallel, the probable signal pathways involved in it, including Grb2 and Ras will be investigated. This project focuses on clarifying the mechanism of pressure overload-induced autophagy from a new perspective, which will provide new insights and the target for prevention and treatment of heart failure.

自噬在心力衰竭的发展中起重要作用，环状RNA影响心力衰竭的发展。我们的预实验发现：机械牵张心肌细胞导致miR-378表达减少，敲除miR-378引起细胞自噬增多；机械牵张刺激心脏成纤维细胞分泌exosomal circSLC8A1增多，而circSLC8A1增加心肌细胞自噬。生物信息学分析显示：circSLC8A1调控miR-378。据此我们推测：exosomal circSLC8A1调控miR-378促进心肌细胞自噬。本研究拟采用心脏压力超负荷模型，通过RIP-qPCR、RNA pull down等技术分步骤研究exosomal circSLC8A1对miR-378及其信号通路的作用；最后研究exosomal circSLC8A1调控miR-378对心肌细胞自噬及心功能的影响。本课题从外泌体介导环状RNA的新视角研究心肌细胞自噬的调控，为探索心力衰竭治疗的新靶点提供一定理论和实验基础。

自噬在心力衰竭的发展中起重要作用，环状RNA影响心力衰竭的发展。但心脏成纤维细胞分泌的外泌体环状RNAs对心肌细胞自噬的作用尚未明确。我们的课题发现：机械牵张显著促进心脏成纤维细胞分泌exosomal circSLC8A1，心脏成纤维细胞通过exosomal circSLC8A1对话心肌细胞。本研究采用荧光共定位等技术阐明exosomal circSLC8A1从CFs分泌、胞吞进入心肌细胞。有趣的是，我们发现心脏成纤维细胞分泌的exosomal circSLC8A1引起心肌细胞自噬显著增多。随后的研究显示：circSLC8A1调控miR-378。机械牵张心肌细胞导致miR-378表达减少，敲除miR-378引起细胞自噬增多。我们进一步研究发现：exosomal circSLC8A1调控miR-378促进心肌细胞自噬。本课题从外泌体介导环状RNA的新视角研究心肌细胞自噬的调控，为探索心力衰竭治疗的新靶点提供一定理论和实验基础。