Piezo1-Mediated TGF-beta2 autocrine loop promotes atrial fibrosis and fibrillation under pressure overload

Abstract Background Atrial fibrillation (AF), the most prevalent clinical arrhythmia, is associated with progressive fibrosis and adverse outcomes. While the mechanosensitive ion channel Piezo1 is implicated in multiple pathologies, its role in AF remains undefined. This study investigates fibroblast-specific Piezo1 signaling in AF pathogenesis. Methods Fibroblast-specific Piezo1 knockout (Piezo1-FKO) mice were generated and subjected to transverse aortic constriction (TAC) to induce pressure overload. AF susceptibility was assessed via programmed electrical stimulation and optical mapping. Differential protein expression was validated in human AF vs. non-AF atrial tissues. Mechanical stretch was applied to fibroblasts, followed by RNA sequencing. Luciferase reporter and ChIP assays were used to dissect transcriptional regulation of TGF-β2. Results Piezo1-FKO mice exhibited reduced atrial fibrosis and AF inducibility post-TAC. Stretch-activated Piezo1 upregulated ATF4, which transcriptionally promoted TGF-β2 expression via direct binding to its promoter. TGF-β2 further amplified fibrotic responses through autocrine signaling. Conclusion We identify a mechano-sensitive "Piezo1/ATF4/TGF-β2" axis in fibroblasts that drives autocrine fibrotic remodeling and AF progression. Targeting Piezo1 may offer a novel AF therapeutic strategy.Schematic illustration of mechanism