Circ_ZNF512-Mediated miR-181d-5p Inhibition Limits Cardiomyocyte Autophagy and Promotes Myocardial Ischemia/Reperfusion Injury through an EGR1/mTORC1/TFEB-Based Mechanism

• Published in: Journal of medicinal chemistry 2022-02, Vol.65 (3), p.1808-1821
• Main Authors: Huang, Chen, Shu, Liliang, Zhang, Hualu, Zhu, Xiaohua, Huang, Gongcheng, Xu, Jing
• Format: Article
• Language: English
• Subjects: Animals; Autophagy - physiology; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Early Growth Response Protein 1 - metabolism; Male; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice; Mice, Inbred C57BL; MicroRNAs - metabolism; Myocardial Reperfusion Injury - metabolism; Myocytes, Cardiac - metabolism; RNA, Circular - metabolism; Signal Transduction - physiology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00745

Studies have shown that circRNAs are important regulatory molecules involved in cell physiology and pathology. Herein, we analyzed the role of circ_ZNF512 in cardiomyocyte autophagy of myocardial ischemia/reperfusion (I/R) injury. A mouse model was induced by ligation of the left anterior descending artery followed by reperfusion. An in vitro model was also developed in cultured cardiomyocytes following hypoxia/reoxygenation (H/R) injury. It was established that EGR1 expression was increased in myocardial tissues of I/R mice and H/R-induced cardiomyocytes. Silencing of circ_ZNF512 attenuated its binding to miR-181d-5p, which in turn impaired the EGR1 expression by targeting its 3′-UTR, thus promoting the autophagy of cardiomyocytes and suppressing cell apoptosis to alleviate myocardial tissue injury. Additionally, the circ_ZNF512/miR-181d-5p/EGR1 crosstalk activated the mTORC1/TFEB signaling pathway, increasing mTORC1 expression while suppressing TFEB expression. Together, circ_ZNF512 knockdown protects against myocardial I/R injury, which may be a potential therapeutic approach for preventing myocardial I/R injury.