SP1-mediated transcriptional repression of SFRP5 is correlated with cardiac fibroblast activation and atrial myocyte apoptosis in the development of atrial fibrillation

Secreted frizzled related protein 5 (SFRP5) is a recognized cardioprotective protein with diminished expression in atrial fibrillation (AF). This study investigates SFRP5's function in AF-related cardiac fibrosis and cardiomyocyte apoptosis, exploring the underlying dysregulation causes. Utilizing C57BL/6 mice, mouse cardiac fibroblasts (CFs), and HC-1 mouse atrial myocyte cell line, AF models were induced by angiotensin Ⅱ (Ang Ⅱ). SFRP5 levels were consistently decreased in plasma samples from clinical patients, modeled mice, and CF culture supernatants. Treatment with recombinant SFRP5 restored its levels, mitigating Ang Ⅱ-induced AF in mice and ameliorating atrial tissue fibrosis and oxidative stress. In vitro, SFRP5 recombinant protein suppressed CF activation and fibrosis-related markers. The study identified Sp1 transcription factor (SP1) binding to the SFRP5 promoter, causing transcriptional repression. SP1 knockdown reinstated SFRP5 levels in mice and CFs, thus suppressing fibrosis. Additionally, SP1 knockdown attenuated Ang Ⅱ-induced apoptosis in HC-1 cells, but this effect was counteracted by concurrent SFRP5 knockdown. In conclusion, this investigation underscores that SP1 mediates SFRP5 loss during AF by transcriptional repression, contributing to fibrosis and myocyte apoptosis. These findings illuminate potential therapeutic interventions targeting the SFRP5-SP1 axis in AF-related cardiac complications.