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.