miR‐448‐3p/miR‐1264‐3p Participates in Intermittent Hypoxic Response in Hippocampus by Regulating Fam76b/hnRNPA2B1

ABSTRACT Background Intermittent hypoxia (IH), as a key pathogenic factor of obstructive sleep apnea syndrome (OSAS), can cause many diseases, such as increased inflammation and oxidative stress, diabetes, cardiovascular disease, and Alzheimer's disease (AD). The response of cells to hypoxia involves multiple levels of regulatory mechanisms, including transcriptional regulation of gene expression, regulation of mRNA stability, post‐transcriptional regulation, and post‐translational modification regulation. Aims The regulation of miRNA and alternative splicing (AS) in neuronal response to intermittent hypoxia deserve further study. Materials & Methods By establishing a mouse model of intermittent hypoxia, we conducted functional studies on key miRNAs and splicing factor using methods such as miRNA sequencing, bioinformatics, and molecular biology. Results In the mouse hippocampus, intermittent hypoxia altered the expression of many miRNAs, with miR‐448‐3p and miR‐1264‐3p changing over the course of more than three time periods. Interestingly, the expression of Fam76b , the common target gene of these two miRNAs, also changed under intermittent hypoxia. Further studies showed that Fam76b may regulate the ratio of Nbr1 and Dph3 transcripts in response to hypoxia by affecting the localization of hnRNPA2B1 protein within cells. Discussion Research into intermittent hypoxia‐induced disorders, including Alzheimer's disease and other neurodegenerative diseases, might benefit from a better understanding of the regulatory mechanisms of miRNA and alternative splicing in hypoxic response at the animal and cell levels. Conclusion This study demonstrates that intermittent hypoxia alters the expression of miR‐448‐3p and miR‐1264‐3p, as well as the localization of the splicing factor hnRNPA2B1 in the cell nucleus. These findings enhance our understanding of the molecular mechanisms of neuronal responses to hypoxia and hold potential implications for treating hypoxia‐related diseases like Alzheimer's disease.