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Atrial fibrillation (AF) is the most common cardiac arrhythmia nowadays. The occurrence of AF is closely associated with obesity. Cadherin‐11 (Cad‐11), as a member of the cadherin family, can make a contribution to diet‐induced obesity and it will be informative to know whether Cad‐11 exerts its effects on atrial remodeling and AF vulnerability in a diet‐induced obesity model. In this study, we demonstrated that the expression of Cad‐11 was significantly upregulated in the left atrium of AF patients with obesity and mice following 16 weeks of high‐fat diet (HFD) feeding. Further confirmed that Cad‐11 could regulate the activity of atrial fibroblasts by participating in inducing proinflammatory cytokines production. At animal levels, we found that although there was a lack of statistical difference in body weight, Cad‐11−/− mice could markedly improve impaired glucose tolerance and hyperlipidemia. Adverse atrial structural remodeling, including atrial enlargement, inflammation, and fibrosis provoked by HFD feeding were mitigated in Cad‐11−/− mice. Mechanistically, Cad‐11 activated mitogen‐activated protein kinases and nuclear factor‐κB for interleukin‐6 production in atrial fibroblasts that may contribute to the atrial fibrosis process in obesity‐related AF, suggesting Cad‐11 might be a new therapeutic target for obesity‐related AF. [ABSTRACT FROM AUTHOR]

Endothelial‐to‐mesenchymal transition (EndMT) was first reported in heart development. Recent studies have shown that EndMT also occurs in the progression of cardiac fibrosis. Herein, we demonstrated a critical role of the Forkhead Box M1 (Foxm1) transcription factor in transforming growth factor beta (TGF‐β)‐induced EndMT in endothelial cells (ECs) and a possible underlying molecular mechanism. Foxm1 was induced in ECs following TGF‐β stimulation. Using both pharmacological and molecular approaches to inhibit Foxm1 function can attenuate the TGF‐β‐induced EndMT and cell migration. In contrast, lentivirus‐mediated overexpression of Foxm1 allowed EndMT to proceed despite the absence of TGF‐β in ECs. Moreover, we found that the activation of the Smad2/3 signaling pathway and EndMT‐related transcription factors played important roles in the pathogenesis of Foxm1‐mediated EndMT. Further analysis revealed that Foxm1 bound to and increased the promoter activity of the Snail gene encoding a critical transcriptional regulator of EndMT. In conclusion, our results identify FOXM1 as a driver of TGF‐β‐induced EndMT and underscore the therapeutic potential of targeting FOXM1 for cardiac fibrosis. We found that the activation of the Smad2/3 signaling pathway and endothelial‐to‐mesenchymal transition (EndMT)‐related transcription factors played important roles in the pathogenesis of Forkhead Box M1 (Foxm1)‐mediated EndMT. Our results identify FOXM1 as a driver of TGF‐β‐induced EndMT and underscore the therapeutic potential of targeting FOXM1 for cardiac fibrosis. [ABSTRACT FROM AUTHOR]