Atrial fibrillation (AF) is characterized by potentiated growth of atrial fibroblasts and excessive deposition of the extracellular matrix. Atrial fibrosis has emerged as a hallmark of atrial structural remodeling linked to AF. Nonetheless, the specific mechanism underlying the progression of atrial fibrosis to AF is still largely unknown. MFGE8 (milk fat globule-EGF factor 8) is a soluble glycoprotein associated with many human diseases. Recently, a number of studies revealed that MFGE8 plays a crucial role in heart disease. Yet, MFGE8 regulation and function in the process of atrial fibrosis and vulnerability to AF remain unexplored. In this study, we found that the expression of MFGE8 was downregulated in the atriums of patients with AF compared with individuals without AF. In addition, the expression of MFGE8 was lower in atriums of angiotensin II (Ang-II)-stimulated rats as compared with the sham group. In vitro, silencing of MFGE8 by small interfering RNA significantly increased Ang-II-induced atrial fibrosis, whereas administration of recombinant human MFGE8 (rhMFGE8) attenuated the atrial fibrosis. Moreover, we found that the activated TGF-β1/Smad2/3 pathway after Ang-II treatment was significantly potentiated by the MFGE8 knockdown but inhibited by rhMFGE8 in vitro. Inhibition of integrin β3 which is the receptor for MFGE8, suppressed the TGF-β1/Smad2/3 activating effects of the MFGE8 knockdown in Ang-II-treated rat atrial fibroblasts. Finally, we administered rhMFGE8 to rats; it attenuated atrial fibrosis and remodeling and further reduced AF vulnerability induced by Ang-II, indicating that MFGE8 might have the potential both as a novel biomarker and as a therapeutic target in atrial fibrosis and AF.

中文翻译：

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MFGE8通过抑制TGF-β1/ Smad2 / 3途径来减轻Ang-II诱导的心房纤维化和对房颤的脆弱性。

心房颤动（AF）的特征在于心房成纤维细胞的生长增强和细胞外基质的过度沉积。心房纤维化已成为与房颤相关的心房结构重塑的标志。尽管如此，仍未完全了解导致心房纤维化发展为房颤的具体机制。MFGE8（乳脂球蛋白-EGF因子8）是与许多人类疾病相关的可溶性糖蛋白。最近，许多研究表明MFGE8在心脏病中起着至关重要的作用。然而，MFGE8在心房纤维化和房颤易感性过程中的调控和功能尚待探索。在这项研究中，我们发现与没有AF的个体相比，患有AF的患者的心房中MFGE8的表达下调。此外，与假手术组相比，血管紧张素II（Ang-II）刺激的大鼠心房中MFGE8的表达较低。在体外，通过小的干扰RNA沉默MFGE8会显着增加Ang-II诱导的心房纤维化，而重组人MFGE8（rhMFGE8）的给药可减轻心房纤维化。此外，我们发现Ang-II处理后激活的TGF-β1/ Smad2 / 3途径在体外被MFGE8敲低显着增强，但被rhMFGE8抑制。抑制整合素β3是MFGE8的受体，抑制了Ang-II处理的大鼠心房成纤维细胞中MFGE8敲低的TGF-β1/ Smad2 / 3活化作用。最后，我们给大鼠施用了rhMFGE8。它减轻了心房纤维化和重塑，并进一步降低了Ang-II引起的房颤易感性，