AIMS Atrial fibrosis is a common feature of atrial fibrillation (AF). Recently, it is reported that osteopontin (OPN) can induce fibrosis in lungs, livers and kidneys. However, its role in atrial fibrosis remains unclear. Here, we sought to determine the involvement of OPN in atrial fibrosis and the underlying mechanisms during this pathological remodeling process. MATERIALS AND METHODS Protein expressions were determined by enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining and immunoblotting. mRNA expressions were detected by qRT-PCR. Cell proliferation was assessed by CCK-8. Left atrial electroanatomical voltage maps were created using PentaRay catheters and a 3-dimensional mapping system. KEY FINDINGS OPN was highly expressed in the circulation of AF patients and was further increased with the progression of AF. In addition, correlation analysis showed that circulating OPN positively related with low-voltage areas (LVAs, a marker of atrial fibrosis) in AF patients. Immunohistological staining and immunoblotting revealed an increased expression of OPN in AF patients who present a higher degree of atrial fibrosis. Furthermore, in vitro studies in cultured human atrial fibroblasts (hAFs) demonstrated that OPN promoted the proliferation of fibroblasts and increased production of collagen I and fibronectin. Mechanistically, the profibrotic effects of OPN on atrial fibroblasts were determined via activating Akt/GSK-3β/β-catenin signaling and suppressing autophagy. SIGNIFICANCE This study uncovered a previously unrecognized profibrotic role of OPN in atrial fibrosis, which was achieved through activation of Akt/GSK-3β/β-catenin signaling pathway and suppression of autophagy, implying a promising therapeutic target in atrial fibrosis and AF.

中文翻译：

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骨桥蛋白通过激活Akt /GSK-3β/β-catenin途径并抑制自噬来诱导心房纤维化。

AIMS心房纤维化是房颤（AF）的共同特征。最近，有报道说骨桥蛋白（OPN）可以在肺，肝和肾中引起纤维化。但是，其在心房纤维化中的作用仍不清楚。在这里，我们试图确定OPN参与房颤的纤维化以及在这种病理重塑过程中的潜在机制。材料与方法通过酶联免疫吸附测定（ELISA），免疫组化染色和免疫印迹测定蛋白表达。通过qRT-PCR检测mRNA表达。通过CCK-8评估细胞增殖。使用PentaRay导管和3维标测系统创建左心房电解剖电压图。主要发现OPN在房颤患者的血液中高度表达，并随着房颤的发展而进一步增加。此外，相关性分析表明，AF患者循环中的OPN与低压区域（心房纤维化的标志物，LVA）呈正相关。免疫组织学染色和免疫印迹显示，在房颤程度较高的房颤患者中，OPN的表达增加。此外，在体外培养的人心房成纤维细胞（hAFs）中的体外研究表明，OPN可以促进成纤维细胞的增殖并增加胶原蛋白I和纤连蛋白的产量。从机制上讲，通过激活Akt /GSK-3β/β-catenin信号传导并抑制自噬，可以确定OPN对心房成纤维细胞的促纤维化作用。重要性本研究揭示了OPN在心房纤维化中先前未被认识的促纤维化作用，