circRNA Hipk3 Induces Cardiac Regeneration after Myocardial Infarction in Mice by Binding to Notch1 and miR-133a
circRNA Hipk3 Induces Cardiac Regeneration after Myocardial Infarction in Mice by Binding to Notch1 and miR-133a
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circRNA Hipk3 通过与 Notch1 和 miR-133a 结合诱导小鼠心肌梗死后心脏再生
DOI：
10.1016/j.omtn.2020.06.024
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发表时间：
2020-09-04
影响因子：
8.8
通讯作者：
Bin, Jianping
中科院分区：
文献类型：
--
作者：
Si, Xiaoyun;Zheng, Hao;Bin, Jianping
心肌发生和血管生成之间的协同作用是心脏再生所必需的。环状RNA（circRNA）在细胞生长和血管生成中起关键作用，但其在心脏再生中的功能尚不清楚。在这项研究中，我们研究了circRNA Hipk 3（circHipk 3）在心脏再生过程中的心肌发生和血管生成中的作用和潜在机制。我们发现circHipk 3在小鼠胎儿或新生儿心脏中过表达。转录因子Gata 4与circHipk 3启动子结合并增加circHipk 3表达。在体外和体内的心肌细胞（CM）增殖抑制circH-ipk 3敲低和增加circHipk 3过表达。此外，circHipk 3过表达促进冠状动脉血管内皮细胞增殖，迁移和管形成能力和随后的血管生成。更重要的是，circHipk 3过表达减轻了心肌梗死（MI）后的心功能障碍并减少了纤维化面积。从机制上讲，circHipk 3通过增加Notch 1胞内结构域（N1 ICD）乙酰化促进CM增殖，从而增加N1 ICD稳定性并防止其降解。此外，circHipk 3作为microRNA（miR）-133a的海绵，促进结缔组织生长因子（CTGF）表达，从而激活内皮细胞。我们的研究结果表明，circHipk 3可能是一个新的治疗靶点，用于预防心肌梗死后心力衰竭。
The synergism between cardiomyogenesis and angiogenesis is essential for cardiac regeneration. Circular RNAs (circRNAs) play pivotal roles in cell growth and angiogenesis, but their functions in cardiac regeneration are not yet known. In this study, we investigated the role and underlying mechanisms of circRNA Hipk3 (circHipk3) in both cardiomyogenesis and angiogenesis during cardiac regeneration. We found that circHipk3 was overexpressed in the fetal or neonatal heart of mice. The transcription factor Gata4 bound to the circHipk3 promoter and increased circHipk3 expression. Cardiomyocyte (CM) proliferation in vitro and in vivo was inhibited by circH-ipk3 knockdown and increased by circHipk3 overexpression. Moreover, circHipk3 overexpression promoted coronary vessel endothelial cell proliferation, migration, and tube-forming capacity and subsequent angiogenesis. More importantly, circHipk3 overexpression attenuated cardiac dysfunction and decreased fibrotic area after myocardial infarction (MI). Mechanistically, circHipk3 promoted CM proliferation by increasing Notch1 intracellular domain (N1ICD) acetylation, thereby increasing N1ICD stability and preventing its degradation. In addition, circHipk3 acted as a sponge for microRNA (miR)-133a to promote connective tissue growth factor (CTGF) expression, which activated endothelial cells. Our findings suggested that circHipk3 might be a novel therapeutic target for preventing heart failure post-MI.