<scp>MCPIP1</scp> promotes atrial remodeling by exacerbating <scp>miR</scp> ‐26a‐5p/ <scp>FRAT</scp> /Wnt axis–mediated atrial fibrosis in a rat model susceptible to atrial fibrillation

Atrial fibrosis plays a critical role in the pathogenesis of atrial fibrillation (AF). Monocyte chemotactic protein-induced protein-1 (MCPIP1), recognized as a functional ribonuclease (RNase), exacerbates cardiac remodeling and contributes to a range of cardiovascular diseases. However, the involvement of MCPIP1 in atrial fibrosis and development of AF, along with its underlying biological mechanisms, remains poorly understood. This study demonstrated that knockdown of MCPIP1 significantly reduced AF inducibility, decreased left atrial diameter, and ameliorated atrial fibrosis, coinciding with reduced FRAT1/2/Wnt/β-catenin signaling. Furthermore, the MCPIP1-D141N mutation attenuated AF vulnerability and atrial remodeling compared to MCPIP1 overexpression in an acetylcholine and calcium chloride (ACh-CaCl₂)-induced rat model of AF. Conversely, overexpression of FRAT1/2 partially reversed the cardioprotective effects of MCPIP1-D141N mutation. Using H9C2 cell lines, we observed that MCPIP1 may induce a transcriptional effect that downregulates miR-26a-5p expression, and luciferase and RNA immunoprecipitation (RIP) assays substantiated the direct interaction between miR-26a-5p and FRAT1/2. Moreover, overexpression of miR-26a-5p countered MCPIP1-induced atrial remodeling and attenuated the progression of AF. In conclusion, these findings indicate that MCPIP1 facilitates atrial remodeling and the progression of AF by exacerbating miR-26a-5p/FRAT/Wnt axis-mediated atrial fibrosis through its RNase activity in an ACh-CaCl₂-induced rat model of AF.