Cardiovascular Center, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
Department of Pathology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
J Transl Med. 2024 Aug 5;22(1):734. doi: 10.1186/s12967-024-05558-0.
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 .
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.
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.
Based on human atrial pathological and molecular analyses, our findings provided evidence that β-catenin was associated with atrial fibrosis and AF progression.
心房颤动（AF）与中风和死亡率增加有关。据报道，在 AF 大鼠中，心房纤维化的过程受β-catenin 调节。然而，AF 患者中这一过程的病理生理机制尚不清楚。本研究旨在使用人右心耳（hRAA）组织研究β-catenin 参与心房纤维化的可能机制。
我们比较了 AF 患者和窦性心律（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讨了β-catenin 在 AF 发展中的可能作用。
首先，心肌细胞间隙连接膜之间的空间在 AF 组中更宽。其次，间隙连接功能相关蛋白 Connexin40 和 Connexin43 的表达降低，而 hRAA 和 AF 组心肌细胞中β-catenin 及其结合伴侣 E-cadherin 的表达增加。第三，β-catenin 在 SR 组的心肌细胞质膜上与 E-cadherin 共定位，而在 AF 组中则分离并积累在细胞内。此外，参与β-catenin 降解的糖原合酶激酶 3β（GSK-3β）和腺瘤性息肉病基因（APC）的表达在 AF 组的 hRAA 组织和心肌细胞中降低。最后，抑制 AF 模型小鼠中的β-catenin 表达可预防心房纤维化和 AF 的发展。
基于人类心房的病理和分子分析，我们的研究结果提供了证据表明β-catenin 与心房纤维化和 AF 进展有关。
