Huang Senlin, Wei Guoquan, Jia Xiaoqian, Tang Zhenquan, Chen Qiqi, Li Chuling, Yan Wen, Jin Ming, Li Xinzhong, Chen Yanmei, Zheng Hao, Chen Guojun, Liao Wangjun, Liao Yulin, Wang Yuegang, Li Jianyong, Bin Jianping
Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China.
Department of Oncology, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China.
Int J Biol Macromol. 2025 Jan;287:138406. doi: 10.1016/j.ijbiomac.2024.138406. Epub 2024 Dec 4.
Ribosome biogenesis (RiBi) is an essential process that controls the protein synthesis rate, but its function in regulating endogenous cardiac regeneration remains unknown. Herein, we investigated the function and underlying mechanism of RiBi-associated circRNAs in cardiomyocyte (CM) proliferation and cardiac regeneration. We used high-throughput sequencing, quantitative PCR and in situ hybridization techniques to identify an adult downregulated circRNA, RiBi-associated circRNA (RBAC), in CMs. A functional study further revealed that RBAC overexpression increased ribosome biogenesis activity and cell cycle progression in CMs, while silencing RBAC decreased ribosome biogenesis activity and cell cycle progression. Moreover, RBAC overexpression induced adult CM proliferation and improved cardiac function after myocardial infarction in adult mice. Mechanistically, RBAC controlled ribosome biogenesis and cell proliferation by regulating the proteasome-dependent degradation of Ddx21, thereby altering the localization of Rps14 and reducing Rb expression. Our findings indicate that RBAC upregulation might be a plausible therapeutic strategy to induce endogenous cardiac regeneration.
核糖体生物合成（RiBi）是控制蛋白质合成速率的一个重要过程，但其在调节内源性心脏再生中的作用仍不清楚。在此，我们研究了与RiBi相关的环状RNA在心肌细胞（CM）增殖和心脏再生中的功能及潜在机制。我们使用高通量测序、定量PCR和原位杂交技术，在心肌细胞中鉴定出一种在成体中表达下调的环状RNA，即与RiBi相关的环状RNA（RBAC）。功能研究进一步表明，RBAC过表达增加了心肌细胞中的核糖体生物合成活性和细胞周期进程，而沉默RBAC则降低了核糖体生物合成活性和细胞周期进程。此外，RBAC过表达诱导成年小鼠心肌梗死后的成年心肌细胞增殖并改善心脏功能。从机制上讲，RBAC通过调节蛋白酶体依赖性的Ddx21降解来控制核糖体生物合成和细胞增殖，从而改变Rps14的定位并降低Rb表达。我们的研究结果表明，上调RBAC可能是诱导内源性心脏再生的一种可行治疗策略。
