外泌体介导的AT1-R/Carabin通路对心肌肥厚预适应的调控作用及其机制

预置的压力超负荷撤离后，心肌出现肥厚预适应现象，对再次压力超负荷起抗肥厚作用，其机制尚待阐明。我们既往报道血管紧张素Ⅱ1型受体（AT1-R）是压力超负荷机械刺激感受器，外泌体是传递胞间信息的重要载体。在前期工作中我们发现，压力超负荷增加外泌体AT1-R表达，肥厚预适应处理降低其表达。功能分析发现，奥美沙坦（AT1-R拮抗剂）、GW4869（外泌体分泌抑制剂）和预适应处理均加强抑肥大因子Carabin的表达，故我们推测外泌体介导的AT1-R/Carabin信号涉及肥厚预适应现象。我们拟采用压力超负荷预适应动物和细胞模型，经基因或药物手段，增强和抑制AT1-R/Carabin水平，阐明外泌体介导的AT1-R/Carabin在肥厚预适应及其下游肥大相关信号中的调控作用与机制。本项目将揭示外泌体介导的AT1-R对心肌重塑的新作用，为心衰早期防治提供新依据。

After withdrawal of preset pressure overload, the myocardium shows hypertrophic preconditioning (HP) to resist hypertrophy induced by subsequent re-exposure of pressure overload. The mechanism of HP remains to be elucidated. We have previously demonstrated that the angiotensin Ⅱ type 1 receptor (AT1-R) is a mechanosensor for pressure overload signal transduction, and exosome is an important platform for intercellular communication. We in our pilot experiments found that pressure overload increased the expression of exosomal AT1-R, while HP reduced it. Further functional analyses demonstrate that olmesartan (AT1-R blocker), GW4869 (exosome inhibitor) or HP administration enhanced the expression of Carabin, a negative regulator of hypertrophy. We thus postulate that exosome-mediated AT1-R/Carabin signaling is critically involved in HP. By establishment of HP model at animal and cellular level, we in this project, with the aid of pharmaceutical and genetical activation/inhibition of AT1-R/Carabin, plan to elucidate The regulatory role and mechanism of exosome-mediated AT1-R/Carabin signaling in myocardial hypertrophic preconditioning and downstream hypertrophy-related signaling molecules. This project is designated to unravel new roles of exosomal AT1-R in myocardial remodeling, and thus to present new insights into early prevention and treatment of heart failure.