Chronic hypoxia-induced upregulation of hsa_circ_0005255 attenuates myocardial injury via targeting hsa-miR-3916/FTO/m6A axis.

Chronic hypoxia initiates compensatory mechanisms to protect the heart. Circular RNAs (circRNAs), a recently identified class of non-coding RNAs, represent a significant portion of mammalian transcriptome. We aimed to explore the underlying mechanisms of circRNA involvement in chronic hypoxia-related cardiovascular diseases. In the presents study, we firstly observed hsa_circ_0005255 was elevated in myocardial samples collected from patients with cyanotic heart disease through using circRNA array sequencing, which was confirmed both in vivo and in vitro. The upregulation of hsa_circ_0005255 reduced the levels of N6-methyladenosine (m6A) modification and protected cardiomyocytes from chronic hypoxia induced injury. Fat mass and obesity-associated protein (FTO), the classic regulator of methylation, was proved to be regulated by hsa_circ_0005255. Further research verified the direct target interactions of hsa_circ_0005255/hsa-miR-3916 and hsa-miR-3916/FTO. Our findings suggested hsa_circ_0005255 played pivotal protective role in cardiomyocytes via hsa-miR-3916/FTO/m6A axis. We also showed that silencing hsa_circ_0005255 increased myocardial apoptosis and worsened ischemia/reperfusion (I/R) injury in vivo. In addition, the expression of hsa_circ_0005255 in clinical myocardial samples showed a significant negative correlation with myocardial enzyme levels and early clinical outcomes. This study elucidates a novel mechanism that hsa_circ_0005255/hsa-miR-3916/FTO-m6A axis is involved in myocardial adaptation to chronic hypoxia, representing a promising therapeutic target for cardiovascular diseases.