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

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.

circPAN3 exerts a profibrotic role via sponging miR-221 through FoxO3/ATG7-activated autophagy in a rat model of myocardial infarction.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Cardiac fibrosis is the scarring process occurs commonly with CVDs impairing the function and structure of heart. Herein, we investigated the role of circPAN3 in the pathogenesis of cardiac fibrosis. METHODS: A rat myocardial infarction (MI) model was constructed to evaluate the role of circPAN3. Expression of circPAN3 in MI was determined, and si-circPAN3 was applied to verify its profibrotic effects. With an in vitro model, cardiac fibroblasts were stimulated by transforming growth factor beta 1 (TGFß1). Immunofluorescent staining was employed to assess the fibrosis-related markers, as well as autophagy activity. CCK-8 and transwell assays were performed to determine cell proliferation and migration. Luciferase reporter assay and RNA pull-down were subjected to verify the interaction of circPAN3/miR-221. The enrichment of FoxO3 on the promoter region of ATG7 was detected using CHIP assay. RESULTS: Elevated circPAN3 was found in rat MI heart tissue, of which knockdown attenuated cardiac fibrosis after MI. In an in vitro model exposing with TGFß1, increasing cell proliferation and migration were observed, whereas these effects were abolished by circPAN3 knockdown, as well as autophagy activity. miR-221 was identified as a target to be involved in circPAN3-mediated cardiac fibrosis after MI. miR-221 negatively regulated FoxO3, thus causing the inhibition of ATG7 transcription. The regulatory network of circPAN3/miR-221/FoxO3/ATG7 in cardiac fibrosis was further determined in vivo. CONCLUSION: circPAN3 exhibited profibrotic effects during autophagy-mediated cardiac fibrosis via miR-221/FoxO3/ATG7 axis, which may serve as potential biomarkers for cardiac fibrosis therapeutics.