CircPAN3 ameliorates myocardial ischaemia/reperfusion injury by targeting miR-421/Pink1 axis-mediated autophagy suppression

Abstract

Cardiovascular diseases are considered the leading cause of death worldwide. Myocardial ischaemia/reperfusion (I/R) injury is recognized as a critical risk factor for cardiovascular diseases. Although increasing advances have been made recently in understanding the mechanisms of I/R injury, they remain largely unknown. In this study, we found that the expression of circPAN3 (circular RNA PAN3) was decreased in a mouse model of myocardial I/R. Overexpression of circPAN3 significantly inhibited autophagy and alleviated cell apoptosis of cardiomyocytes, which was further verified in vivo by decreased autophagic vacuoles and reduced myocardial infarct sizes. Moreover, miR-421 (microRNA-421) was identified as a downstream target involved in circPAN3-mediated myocardial I/R injury. Additionally, miR-421 could negatively regulate Pink1 (phosphatase and tensin homologue-induced putative kinase 1) via a direct binding relationship. Furthermore, the mitigating effects of circPAN3 overexpression on myocardial I/R injury by suppressing autophagy and apoptosis were abolished by knockdown of Pink1. Our findings reveal a novel role for circPAN3 in modulating autophagy and apoptosis in myocardial I/R injury and the circPAN3–miR-421–Pink1 axis as a regulatory network, which might provide potential therapeutic targets for cardiovascular diseases.

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Fig. 1: Enhanced autophagy and downregulation of circPAN3 were observed in the mouse model of myocardial I/R injury.
Fig. 2: Overexpression of circPAN3 alleviated myocardial I/R injury and inhibited autophagy.
Fig. 3: CircPAN3 relieved H/R-induced myocardial damage and suppressed autophagy and apoptosis.
Fig. 4: CircPAN3 acts as a sponge of miR-421.
Fig. 5: miR-421 reversed the protective effects of circPAN3 on H/R-induced cardiomyocyte damage.
Fig. 6: Pink1 was a direct target of miR-421.
Fig. 7: CircPAN3 regulated myocardial I/R injury by targeting the miR-421/Pink1 axis.

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Funding

This work was supported by Hunan Provincial Natural Science Foundation Youth Fund (No. 2020JJ5945).

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Guarantor of integrity of the entire study, study concepts, study design and manuscript review: FL. Definition of intellectual content and literature research: S-SB. Experimental studies and manuscript preparation: C-LZ and T-YL. Data acquisition: C-LZ. Data analysis: C-LZ and SAS. Statistical analysis: T-YL. Manuscript editing: SAS.

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Correspondence to Fei Li.

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All animal procedures were approved by the Institutional Animal Care and Use Committee of Xiangya Hospital of Central South University and conducted in accordance with the National Institutes of Health guidelines.

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Zhang, C., Long, T., Bi, S. et al. CircPAN3 ameliorates myocardial ischaemia/reperfusion injury by targeting miR-421/Pink1 axis-mediated autophagy suppression. Lab Invest (2020). https://doi.org/10.1038/s41374-020-00483-4

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