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

Abstract

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.

• Authors: Chen Huang, Liliang Shu, Hualu Zhang, Xiaohua Zhu, Gongcheng Huang, Jing Xu
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 3 Pg. 1808-1821 (02 10 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35041407 (Publication Type: Journal Article)

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Early Growth Response Protein 1
• Egr1 protein, mouse
• MicroRNAs
• RNA, Circular
• Tcfeb protein, mouse
• mirn181 microRNA, mouse
• Mechanistic Target of Rapamycin Complex 1

Topics

• 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, Inbred C57BL
• MicroRNAs (metabolism)
• Myocardial Reperfusion Injury (metabolism)
• Myocytes, Cardiac (metabolism)
• RNA, Circular (metabolism)
• Signal Transduction (physiology)