MiR-21-3p regulation FGFR1/FGF21/PPARγ pathway induces atrial fibrosis by targeting FGFR1 in diabetes

Background A relationship between the abundance of epicardial adipose tissue (EAT) and the risk of atrial fibrillation (AF) in diabetes mellitus (DM) has been reported. And browning of EAT might be a novel approach for prevention or treatment in AF by adjusting atrial fibrosis. MicroRNA-21 (miR-21) is one of the most important miRs, and previous studies have shown that it is a regulatory factor in atrial fibrosis and AF. The aim of this study was to examine the role of different subtypes of miR-21 in EAT browning and atrial fibrosis under hyperglycemia conditions. Methods The expression of serum hsa-miR-21-3p and hsa-miR-21-5p in patients with DM and/or AF were determined by quantitative reverse transcription-polymerase chain reaction. And normal C57BL/6 wild type (WT) and miR-21 knockout (KO) mice were used to establish the diabetic model by intraperitoneal injection of streptozotocin (STZ). In vitro, The EAT adipocytes from miR-21 KO mice were cultured and transfected with miR-21-3p mimic or miR-21-5p mimic and co-cultured with atrial fibroblasts in both HG or LG conditions. The browning of EAT and the fibrosis of fibroblasts were assessed by western blotting, immunofluorescence, Masson staining, and ELISA. Finally, the gain- and loss-of-function experiments were used to identified fibroblast growth factor receptor 1 (FGFR1) as the target gene of miR-21-3p, and the regulatory pathway of miR-21-3p FGFR1, fibroblast growth factor 21 (FGF21) and peroxisome proliferator-activated receptor gamma (PPARγ) that controlled EAT browning and participates the process of hyperglycemia-induced atrial fibrosis. Results In patients with DM and/or AF, serum hsa-miR-21-3p, instead of hsa-miR-21-5p, was significantly up-regulated. And miR-21 KO clearly ameliorated the atrial fibrosis in the diabetic mice. miR-21-3p as a key regulator that controls EAT browning and participates in atrial fibrosis under hyperglycemia conditions. Moreover, our gain- and loss-of-function experiments showed that FGFR1, as a direct target of miR-21-3p identified a regulatory pathway in EAT adipocytes consisting of miR-21-3p, FGFR1, FGF21 and PPARγ. Conclusions MiR-21-3p regulated EAT browning and participates the process of hyperglycemia-induced atrial fibrosis by targeting FGFR1/FGF21/PPARγ pathway.