CircRNA Samd4 induces cardiac repair after myocardial infarction by blocking mitochondria-derived ROS output

作者：Zheng, Hao; Huang, Senlin; Wei, Guoquan; Sun, Yili; Li, Chuling; Si, Xiaoyun; Chen, Yijin; Tang, Zhenquan; Li, Xinzhong; Chen, Yanmei; Liao, Wangjun; Liao, Yulin; Bin, Jianping^*

来源：Molecular Therapy, 2022, 30(11): 3477-3498.

DOI：10.1016/j.ymthe.2022.06.016

• HEART REGENERATION
• TRIGGERS
• PROTEIN
• SYSTEM
• VDAC1
• VCP
• P97

Reactive oxygen species (ROS) derived from oxygen-dependent mitochondrial metabolism are the essential drivers of cardio-myocyte (CM) cell-cycle arrest in adulthood. Mitochondria -local-ized circular RNAs (circRNAs) play important roles in regulating mitochondria-derived ROS production, but their functions in cardiac regeneration are still unknown. Herein, we investigated the functions and underlying mechanism of mitochondria -local-ized circSamd4 in cardiac regeneration. We found that circ-Samd4 was selectively expressed in fetal and neonatal CMs. The transcription factor Nrf2 controlled circSamd4 expression by binding to the promoter of circSamd4 host gene. CircSamd4 overexpression reduced while circSamd4 silenced increased mitochondrial oxidative stress and subsequent oxidative DNA damage. Moreover, circSamd4 overexpression induced CM pro-liferation and prevented CM apoptosis, which reduced the size of the fibrotic area and improved cardiac function after myocardial infarction (MI). Mechanistically, circSamd4 reduced oxidative stress generation and maintained mitochondrial dynamics by inducing the mitochondrial translocation of the Vcp protein, which downregulated Vdac1 expression and prevented the mito-chondrial permeability transition pore (mPTP) from opening. Our findings suggest that circSamd4 is a novel therapeutic target for heart failure after MI.

• 单位
  南方医科大学