Dysregulation of adipocytokines via the hsa-miR-548ay-3p/PPARγ signaling pathway leads to cardiac fibrosis.

Cardiac fibrosis is a chief cause of atrial fibrillation (AF), yet its mechanism is not fully understood. Our previous study found that fibrosis-related adipocytokines were dysregulated in epicardial adipose tissue (EAT) from patients with AF. The present study explored the factors inducing adipocytokine dysregulation and the mechanism by which this dysregulation leads to cardiac fibrosis. The effects of inhibition of PPARγ-induced adipocytokine dysregulation on cardiac fibroblasts (CFs) were investigated by co-culturing with conditioned medium (CM). miRNA targeting PPARγ was screened by combining the TargetScan database, our previous miRNA sequencing data, and validation in EAT samples. The function of hsa-miR-548ay-3p was explored using in vitro and in vivo experiments. The mechanism underlying hsa-miR-548ay-3p/ PPARγ/adipocytokine dysregulation-induced CFs activation was explored by RNA sequencing and validated using in vitro experiments. PPARγ was decreased in EAT from patients with AF, and CM of EAT from patients with AF activated CFs. Inhibition of PPARγ resulted in adipocytokines dysregulation, which then induced the activation of CFs. hsa-miR-548ay-3p induced adipocytokines dysregulation by targeting PPARγ, with this dysregulation resulting in cardiac fibrosis via the TGF-β1/SMAD2/3 signaling pathway. In conclusion, we found that hsa-miR-548ay-3p/PPARγ-induced adipocytokine dysregulation activates CFs, resulting in cardiac fibrosis.