Advanced glycation end products enhance human atrial fibroblast activity through activation of interferon/signal transducer and activator of transcription signaling

Background: Diabetes mellitus and metabolic disorders increase the risk of atrial fibrillation with cardiac electrical and structural remodeling. Advanced glycation end products (AGEs) and their receptor (RAGE) play a critical role in the pathogenesis of diabetes mellitus cardiomyopathy and contribute to atrial fibrogenesis, leading to atrial myopathy. This study elucidated the role of AGEs in atrial fibrogenesis and explored the underlying mechanisms. Methods: Human atrial fibroblasts were treated with AGE–bovine serum albumin (AGE–BSA, 100 μg/mL for 48 h) in the presence or absence of an anti-RAGE neutralizing antibody (RAGE Ab; 5 μg/mL for 48 h). RNA deep sequencing, patch-clamp electrophysiology, and Western blot analyses were performed to assess gene expression, electrical activity, and protein signaling pathways. Results: A total of 40 genes were differentially expressed in AGE-BSA-treated human atrial fibroblasts compared with controls, with 31 genes upregulated and 9 downregulated. A reactome pathway enrichment analysis revealed significant upregulation of pathways related to “Interferon (IFN) alpha/beta signaling,” “Interferon signaling,” “Cytokine signaling in immune system,” “Immune system,” “2′-5′-oligoadenylate synthetase (OAS) antiviral response,” “Interferon-stimulated gene 15 (ISG15) antiviral mechanism,” “Interferon gamma signaling,” and “O-linked glycosylation of mucins” and involvement of the IFN/signal transducer and activator of transcription (STAT)/OAS inflammatory signaling pathways, suggesting that AGE-BSA treatment activated IFN/STAT signaling. Western blot and patch-clamp analyses further demonstrated that AGE treatment activated downstream STAT3/transient receptor potential canonical (TRPC) channel/IP3 receptor signaling and increased TRPC current. Conclusions: AGEs may modulate atrial fibroblast function by activating downstream IFN/STAT signaling pathways and increasing TRPC current activity.