Circular RNA‐circLRP6 protects cardiomyocyte from hypoxia‐induced apoptosis by facilitating hnRNPM‐mediated expression of FGF‐9

Coronary atherosclerosis‐induced myocardial ischemia leads to cardiomyocyte apoptosis. The regulatory mechanisms for cardiomyocyte apoptosis have not been fully understood. Circular RNAs are non‐coding RNAs which play important roles in heart function maintenance and progression of heart diseases by regulating gene transcription and protein translation. Here, we reported a conserved cardiac circular RNA, which is generated from the second exon of LRP6 and named circLRP6 2‐2 . CircLRP6 2‐2 can protect cardiomyocyte from hypoxia‐induced apoptosis. The expression of circLRP6 2‐2 in cardiomyocytes was down‐regulated under hypoxia, while forced expression of circLRP6 2‐2 inhibited cell apoptosis. Normally, circLRP6 2‐2 was mainly localized in the nucleus. Under hypoxia, circLRP6 2‐2 is associated with heterogeneous nuclear ribonucleoprotein M (hnRNPM) to be translocated into the cytoplasm. It recruited hnRNPM to fibroblast growth factor 9 (FGF9) mRNA to enhance the expression of FGF9 protein, promoting hypoxia‐adaption and viability of cardiomyocytes. In summary, this study uncovers a new inhibitor of apoptosis and reveals a novel anti‐apoptotic pathway composed of circLRP6 2‐2 , hnRNPM, and FGF9, which may provide therapeutic targets for coronary heart disease and ischemic myocardial injury.