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.

中文翻译：

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环状RNA-circLRP6通过促进hnRNPM介导的FGF-9表达来保护心肌细胞免受缺氧诱导的细胞凋亡

冠状动脉粥样硬化引起的心肌缺血导致心肌细胞凋亡。心肌细胞凋亡的调节机制尚未完全清楚。环状RNA是非编码RNA，通过调节基因转录和蛋白质翻译，在心脏功能维持和心脏病进展中发挥重要作用。在这里，我们报道了一个保守的心脏环状RNA，它是由LRP6的第二个外显子产生的，命名为circLRP6 ^2-2。CircLRP6 ^2-2可以保护心肌细胞免受缺氧诱导的细胞凋亡。^{缺氧条件下心肌细胞中circLRP6 2-2}的表达下调，而circLRP6 ^2-2的强制表达抑制细胞凋亡。通常，circLRP6 ^2-2主要位于细胞核中。在缺氧条件下，circLRP6 ^2-2与异质核核糖核蛋白 M (hnRNPM) 相关，易位到细胞质中。它将 hnRNPM 募集到成纤维细胞生长因子 9 (FGF9) mRNA 上，以增强 FGF9 蛋白的表达，促进心肌细胞的缺氧适应和活力。^{综上所述，本研究发现了一种新的凋亡抑制剂，揭示了一条由circLRP6 2-2} 、hnRNPM和FGF9组成的新的抗凋亡通路，可能为冠心病和缺血性心肌损伤提供治疗靶点。