心肌细胞分泌外泌体AT1-R促进机械应力引起心肌纤维化的作用和机制研究

Mechanical stress could cause myocardial remodeling independent of AngiotensinII (AngII) ，the detailed molecular mechanism remains elusive.Our previous study found that heat shock transcription factor 1 (HSF1) could suppress cardiac fibrosis induced by mechanical stress, Moreover, Mechanical stress could cause significant cardiac fibrosis and stimulate the secretion of Angiotensin II type-1 receptor(AT1-R)-containing exosomes in the heart of mice lack of endogenous AngII(ATG-/- mice), which could be inhibited by the exosomes inhibitor GW4869 and inverse agonist of AT1-R olmersatan. Accordingly, we speculate that mechanical stress could cause cardiac fibrosis independently of AngII, and AT1-R containing exosomes plays a pivotal role in the mediating of this process. This project is scheduled to explore the role of AT1-R containing exosomes derived from cardiomyocytes in the regulation of the cardiac fibrosis induced by mechanical stress with the model of ATG-/- mice、AT1-R CKO mice and cardiac fibroblasts, and further clarify the interaction between the AT1-R containing exosomes and HSF1 including the downstream signaling pathway changes. This project will focus on elucidating the noncanonical mechanisms of cardiac fibrosis induced by mechanical stress and provide new insights for the prevention and treatment of pathological cardiac remodeling caused by hypertension.

机械应力可不依赖于血管紧张素II（AngII）引起心肌重构，其具体分子机制未明。我们前期研究发现热休克转录因子1（HSF1）可抑制机械应力引起的心肌纤维化；并且在内源性AngII缺失(ATG-/-)小鼠中机械应力可显著增加外泌体AT1-R的分泌，引起明显心肌纤维化；该效应可被外泌体抑制剂 GW4869和血管紧张素II受体1 （AT1-R）的反向激动剂奥美沙坦所抑制。据此推测机械应力不依赖于AngII引起心肌纤维化，外泌体AT1-R在其中起关键作用。本研究拟在ATG-/-小鼠、AT1-R CKO敲除小鼠及成纤维细胞中建立机械应力模型，探讨机械应力作用下心肌细胞分泌的外泌体AT1-R是否直接参与心肌纤维化及其机制，阐明外泌体AT1-R与HSF1之间相互作用关系。本研究有助于阐述机械应力导致心肌纤维化的非经典机制，为高血压导致心肌重构提供新的防治思路。

本研究通过拟在ATG-/-小鼠、AT1-R CKO敲除小鼠及成纤维细胞中建立机械应力模型，探讨机械应力作用下心肌细胞分泌的外泌体AT1-R是否直接参与心肌纤维化及其机制，研究结果发现外泌体 AT1-R 以及HSF1均参与了机械应力不依赖于 AngII 引起的心肌纤维化病理过程，并且外泌体AT1-R可能通过HSF1参与调控在机械应力不依赖于 AngII 引起的心肌纤维，该研究结果有助于阐述机械应力导致心肌纤维化的非经典机制，为高血压导致的心肌重构提供新的防治思路。