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Abstract：
BACKGROUND: Atrial fibrillation (AF) is associated with increased risk of stroke and mortality. It has been reported that the process of atrial fibrosis was regulated by β-catenin in rats with AF. However, pathophysiological mechanisms of this process in human with AF remain unclear. This study aims to investigate the possible mechanisms of β-catenin in participating in the atrial fibrosis using human right atrial appendage (hRAA) tissues .
METHODS: We compared the difference of β-catenin expression in hRAA tissues between the patients with AF and sinus rhythm (SR). The possible function of β-catenin in the development of AF was also explored in mice and primary cells.
RESULTS: Firstly, the space between the membrane of the gap junctions of cardiomyocytes was wider in the AF group. Secondly, the expression of the gap junction function related proteins, Connexin40 and Connexin43, was decreased, while the expression of β-catenin and its binding partner E-cadherin was increased in hRAA and cardiomyocytes of the AF group. Thirdly, β-catenin colocalized with E-cadherin on the plasma membrane of cardiomyocytes in the SR group, while they were dissociated and accumulated intracellularly in the AF group. Furthermore, the expression of glycogen synthase kinase 3β (GSK-3β) and Adenomatous Polyposis Coli (APC), which participated in the degradation of β-catenin, was decreased in hRAA tissues and cardiomyocytes of the AF group. Finally, the development of atrial fibrosis and AF were proved to be prevented after inhibiting β-catenin expression in the AF model mice.
CONCLUSIONS: Based on human atrial pathological and molecular analyses, our findings provided evidence that β-catenin was associated with atrial fibrosis and AF progression.
METHODS: We compared the difference of β-catenin expression in hRAA tissues between the patients with AF and sinus rhythm (SR). The possible function of β-catenin in the development of AF was also explored in mice and primary cells.
RESULTS: Firstly, the space between the membrane of the gap junctions of cardiomyocytes was wider in the AF group. Secondly, the expression of the gap junction function related proteins, Connexin40 and Connexin43, was decreased, while the expression of β-catenin and its binding partner E-cadherin was increased in hRAA and cardiomyocytes of the AF group. Thirdly, β-catenin colocalized with E-cadherin on the plasma membrane of cardiomyocytes in the SR group, while they were dissociated and accumulated intracellularly in the AF group. Furthermore, the expression of glycogen synthase kinase 3β (GSK-3β) and Adenomatous Polyposis Coli (APC), which participated in the degradation of β-catenin, was decreased in hRAA tissues and cardiomyocytes of the AF group. Finally, the development of atrial fibrosis and AF were proved to be prevented after inhibiting β-catenin expression in the AF model mice.
CONCLUSIONS: Based on human atrial pathological and molecular analyses, our findings provided evidence that β-catenin was associated with atrial fibrosis and AF progression.
摘要：
背景：心房颤动（AF）与卒中风险和死亡率增加相关。据报道，房颤大鼠心房纤维化的过程受β-catenin调节。然而,人类房颤患者这一过程的病理生理机制尚不清楚。本研究旨在探讨β-catenin参与人右心耳（hRAA）组织心房纤维化的可能机制。
方法：我们比较了房颤和窦性心律（SR）患者hRAA组织中β-catenin表达的差异。还在小鼠和原代细胞中探索了β-catenin在AF发展中的可能功能。
结果：首先，AF组心肌细胞缝隙连接膜之间的间隙较宽。其次,缝隙连接功能相关蛋白的表达，Connexin40和Connexin43减少，而β-catenin及其结合伴侣E-cadherin在hRAA和AF组心肌细胞中的表达增加。第三，β-catenin与E-cadherin共定位在SR组心肌细胞的质膜上，而在房颤组，它们在细胞内分离和积累。此外，糖原合成酶激酶3β（GSK-3β）和腺瘤性结肠息肉病（APC）的表达，参与β-连环蛋白的降解，在AF组的hRAA组织和心肌细胞中降低。最后,在AF模型小鼠中，抑制β-catenin的表达后，心房纤维化和AF的发展被证明可以被阻止。
结论：基于人类心房病理和分子分析，我们的研究结果提供了β-catenin与心房纤维化和房颤进展相关的证据.
方法：我们比较了房颤和窦性心律（SR）患者hRAA组织中β-catenin表达的差异。还在小鼠和原代细胞中探索了β-catenin在AF发展中的可能功能。
结果：首先，AF组心肌细胞缝隙连接膜之间的间隙较宽。其次,缝隙连接功能相关蛋白的表达，Connexin40和Connexin43减少，而β-catenin及其结合伴侣E-cadherin在hRAA和AF组心肌细胞中的表达增加。第三，β-catenin与E-cadherin共定位在SR组心肌细胞的质膜上，而在房颤组，它们在细胞内分离和积累。此外，糖原合成酶激酶3β（GSK-3β）和腺瘤性结肠息肉病（APC）的表达，参与β-连环蛋白的降解，在AF组的hRAA组织和心肌细胞中降低。最后,在AF模型小鼠中，抑制β-catenin的表达后，心房纤维化和AF的发展被证明可以被阻止。
结论：基于人类心房病理和分子分析，我们的研究结果提供了β-catenin与心房纤维化和房颤进展相关的证据.
