心房肌细胞外泌体lncRNA-DLX6-AS1调控房颤心房纤维化机制研究

外泌体可负载lncRNA以旁分泌途径实现心肌细胞与成纤维细胞间信息交流。我们前期研究发现：快速起搏心房肌细胞释放的外泌体可激活心房成纤维细胞，使其TGFβ1表达明显增加；转录组测序和生物信息学预测提示，外泌体lncRNA-DLX6-AS1能够通过调控成纤维细胞TGFβ1表达，引起心房纤维化；沉默DLX6-AS1再起搏的心房肌细胞外泌体不能激活成纤维细胞，且不再使TGFβ1表达上调。我们提出假设：房颤时心房肌细胞源性外泌体DLX6-AS1可能通过结合成纤维细胞内miR-26a或互作蛋白调控TGFβ1表达，促进心房纤维化。本项目拟：①证实心房肌细胞外泌体DLX6-AS1可进入并激活成心房成纤维细胞；②阐明外泌体DLX6-AS1调控心房成纤维细胞TGFβ1表达的分子机制；③在体验证心房肌细胞外泌体DLX6-AS1能够引起心房纤维化，促使房颤发生。本研究将从外泌体环节揭示房颤心房纤维化新机制。

Exosomal long non-coding RNAs (lncRNAs) mediate cellular communication between cardiomyocytes and fibroblasts via paracrine manner. Our previous studies found that exosomes secreted from tachypacing neonatal atrial myocytes activated atrial fibroblasts and significantly upregulated transforming growth factor-β1 (TGF-β1). Meanwhile, the results of RNA-Seq and bioinformatical analysis indicated that exosomal lncRNA-DLX6-AS1 released from tachypacing atrial myocytes could promote atrial fibrosis via regulating TGFβ1. With the knockdown of DLX6-AS1, the exosomes released from tachypacing atrial myocytes could not activate myofibroblasts and upregulate the expression of TGFβ1. Therefore, we hypothesize that DLX6-AS1 derived from atrial myocytes could upregulate TGFβ1 expression and activate atrial fibroblasts by connecting the miR-26a or the interaction protein, which eventually contributed to atrial fibrosis. The present study mainly focuses on the following three aspects: ①to verify the DLX6-AS1 released from atrial myocytes could enter into and activate atrial fibroblasts; ②to reveal the underlying modulatory mechanisms of exosomal DLX6-AS1 on TGFβ1 expression; ③to elucidate the role of exosomal DLX6-AS1 secreted by atrial myocytes in atrial fibrosis and occurrence of atrial fibrillation in vivo. Our work may provide new insights into the potential role and molecular mechanisms of exosomes in regulating atrial fibrosis.