心肌成纤维细胞来源的外泌体AT1-R通过EPAC1介导病理性心肌肥厚的机制研究

外泌体在病理性心肌肥厚的发生发展中具有重要作用，但其具体机制尚不明确。我们前期研究发现，心肌成纤维细胞可分泌含有功能性血管紧张素II受体1（AT1-R）的外泌体，通过旁分泌作用于心肌细胞，诱导心肌细胞环腺苷酸激活的交换蛋白1（EPAC1）表达上调以及心肌细胞肥大。因此，我们推测EPAC1介导了心肌成纤维细胞来源的外泌体AT1-R诱导的病理性心肌肥厚。本研究拟利用AT1-R-/-小鼠，在体内外构建压力超负荷模型，通过基因修饰或药物干预调节EPAC1的表达或活性，检测外泌体AT1-R与EPAC1的相互关系以及心肌肥厚相关信号通路表达变化，探讨心肌成纤维细胞来源的外泌体AT1-R通过EPAC1介导病理性心肌肥厚的分子机制。本研究将建立起心肌成纤维细胞与心肌细胞间新的对话机制，为病理性心肌肥厚的诊治提供理论依据。

Exosomes play an important role in the development of pathological cardiac hypertrophy, but the exact mechanism is still unknown. Our previous study found that cardiac fibroblasts can secrete exosomes containing functional angiotensin II receptor 1 (AT1-R), which induced the upregulation of exchange protein1 directly activated by cyclic AMP (EPAC1) expression and cardiac hypertrophy through paracrine effects on cardiomyocytes. Thus, we hypothesize that cardiac fibroblast-derived exosomal AT1-R induces pathological cardiac hypertrophy mediated by EPAC1. In this study, pressure overload model was employed using AT1-R-/- mice in vivo and in vitro, and the expression or activity of EPAC1 was regulated by gene modification or pharmacological intervention. Then, the relationship between exosomal AT1-R and EPAC1 and the expression of cardiac hypertrophy-related signaling pathways were examined. The molecular mechanism of cardiac fibroblast-derived exosomal AT1-R induced pathological cardiac hypertrophy mediated by EPAC1 will be discussed. This study will establish a new crosstalk between cardiac fibroblasts and cardiomyocytes, providing a theoretical basis for the diagnosis and treatment of pathological cardiac hypertrophy.