Atrial structural remodeling takes on a critical significance to the occurrence and maintenance of atrial fibrillation (AF). As revealed by recent data, insulin-like growth factor-1 receptor (IGF-1R) plays a certain role in tissue fibrosis. In this study, the mechanism of IGF-1R in atrial structural remodeling was examined based on in vivo and in vitro experiments. First, cluster analysis of AF hub genes was conducted, and then the molecular mechanism was proposed by which IGF-1R regulates myocardial fibrosis via the PI3K/Akt/FoxO3a pathway. Subsequently, the mentioned mechanism was verified in human cardiac fibroblasts (HCFs) and rats transduced with IGF-1 overexpression type 9 adeno-associated viruses. The results indicated that IGF-1R activation up-regulated collagen Ⅰ protein expression and Akt phosphorylation in HCFs and rat atrium. The administration of LY294002 reversed the above phenomenon, improved the shortening of atrial effective refractory period, and reduced the increased incidence of AF and atrial fibrosis in rats. The transfection of FoxO3a siRNA reduced the anti-fibrotic effect of LY294002 in HCFs. The above data revealed that activation of IGF-1R takes on a vital significance to atrial structural remodeling by facilitating myocardial fibrosis and expediting the occurrence and maintenance of AF through the regulation of the PI3K/Akt/FoxO3a signaling pathway.

中文翻译：

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IGF-1R通过PI3K/Akt/FoxO3a通路调节心房颤动心肌纤维化的机制

心房结构重塑对于心房颤动（AF）的发生和维持具有至关重要的意义。最新数据显示，胰岛素样生长因子1受体（IGF-1R）在组织纤维化中发挥一定作用。本研究通过体内和体外实验研究了IGF-1R在心房结构重塑中的机制。首先对AF枢纽基因进行聚类分析，提出IGF-1R通过PI3K/Akt/FoxO3a通路调节心肌纤维化的分子机制。随后，上述机制在人心脏成纤维细胞（HCF）和用 IGF-1 过表达 9 型腺相关病毒转导的大鼠中得到验证。结果表明，IGF-1R激活上调HCF和大鼠心房中Ⅰ型胶原蛋白表达和Akt磷酸化。LY294002的给药逆转了上述现象，改善了心房有效不应期的缩短，降低了大鼠房颤和心房纤维化发生率的增加。FoxO3a siRNA 的转染降低了 LY294002 在 HCF 中的抗纤维化作用。上述数据表明，IGF-1R的激活通过调节PI3K/Akt/FoxO3a信号通路促进心肌纤维化并加速AF的发生和维持，对心房结构重塑具有重要意义。