Hyperthermia upregulates exosomal miR-210-3p to target GPD1L activating PI3K/AKT pathway and promoting atrial...

This study seeks to examine the role of miR-210-3p, delivered by atrial myocyte-derived exosomes, in the progression of atrial fibrosis after hyperthermia.

Firstly, by conducting a bioinformatics analysis on the miRDB, miRTarbase, and TargetScan databases, multiple potential target genes of miR-210-3p were identified. Further analysis with the GeneCards database pinpointed GPD1L as a crucial gene related to atrial fibrosis. Subsequently, the expression pattern of GPD1L was analyzed using The Human Protein Atlas database, which showed that GPD1L was highly expressed in myocardial cells. The GSE31821 dataset from the GEO database was further analyzed, revealing significant gene expression differences between atrial fibrillation (AF) patients and sinus rhythm controls, with enrichment analysis identifying key fibrosis-related pathways. Then, an AF cell model was established and exposed to hyperthermia to simulate the effects of insufficient radiofrequency ablation (IRFA).

The results demonstrated that hyperthermia significantly increased the expression of miR-210-3p from exosomes of AC16 atrial myocytes. Co-culture experiments with human cardiac fibroblasts (HCFs) showed that miR-210-3p directly targeted and downregulated GPD1L, thereby activating the PI3K/AKT signaling pathway and promoting the expression of fibrosis-related markers α-SMA, collagen I, and III. Further validation revealed that inhibiting miR-210-3p or overexpressing GPD1L could reverse these fibrotic effects, while GPD1L knockdown significantly enhanced the activation of the PI3K/AKT pathway. Additionally, the PI3K/AKT inhibitor LY294002 effectively suppressed pro-fibrotic effects.

These findings underscore the crucial role of miR-210-3p in exosomes derived from cardiomyocytes in atrial fibrosis following IRFA through GPD1L, providing new potential targets and mechanisms for the treatment of AF-related fibrosis.