心肌干细胞经IGF-1/STAT/miR-155通路下调AT1R改善心肌梗死后心电生理稳定性机理研究

Our previous studies demonstrated that cardiac stem cells transplantation could significantly improve electrophysiological stability and ventricular fibrillation threshold post myocardial infarction in rats, and this effect was closely associated with the inhibition of Angiotensin II Type 1 Receptor (AT1R). There was a remarkable decrease of the level of AT1R post CSCs transplantation. However, specific mechanisms involved remained unclear. Existed evidence reveals that miR-155 can directly downregulate AT1R. Our preliminary experiment showed that CSCs presented a notable secretion of insulin like growth factor 1(IGF-1) in vitro, and both IGF-1, STAT and miR-155 expression were significantly increased in the cardiac tissue after CSCs transplantation, In this study. we tried to investigate whether CSCs could downregulate AT1R via IGF-1/STAT/miR-155 pathway in vitro, and validate the role of IGF-1/STAT/miR-155 signaling pathway in improving electrophysiological stability and ventricular fibrillation threshold after myocardial infarction post CSCs transplantation in vivo. This study will be beneficial for the clarification of the underlying mechanisms of the anti-arrhythmic function of CSCs, and it will provide the experimental and theoretical basis for the clinical application of CSCs therapy in the treatment of myocardial infarction.

我们前期研究发现心肌干细胞（CSCs）移植能够显著改善大鼠心肌梗死后心电生理稳定性和提高室颤阈值，且此效应与抑制血管紧张素II 1型受体(AT1R) 密切相关，但CSCs移植导致AT1R表达下调的具体机制未明。证据显示miR-155能够靶向下调AT1R。我们预实验发现CSCs在体外分泌IGF-1显著增高，且CSCs移植后心脏组织中IGF-1、STAT和 miR-155的表达量均明显增加。本项目拟以IGF-1/STAT/miR-155通路为切入点：在体外实验明确CSCs是否经IGF-1/STAT/miR-155通路下调AT1R的基础上，再通过体内实验确立IGF-1/STAT/miR-155通路在CSCs改善心肌梗死后心电生理稳定性和提高室颤阈值中的作用。研究结果将有助于阐明CSCs抗心律失常的作用机理，同时为CSCs治疗心肌梗死的临床应用提供理论和实验依据。

干细胞移植能够治疗心肌梗死后并显著改善心电生理稳定性和提高室颤阈值，我们课题组在前期观察到该效应与明显下调AT1R 有关，继而进一步研究了调节AT1R 的相关分子机制，同时对miR-155 抑制AT1R，IGF-1 抑制AT1R等方面进行了心肌梗死后心电生理稳定性和提高室颤阈值的研究，明确了此效应与抑制血管紧张素II 1型受体(AT1R) 密切相关。进而我们在体外实验明确了IGF-1/STAT/miR-155通路下调AT1R的基础，同时进一步通过体内实验确立IGF-1/STAT/miR-155通路在改善心肌梗死后心电生理稳定性和提高室颤阈值中的作用。本研究结果阐述了IGF-1 经由STAT 上调心肌细胞内miR-155 的表达, miR-155通过下调AT1R 阻断了ANG-Ⅱ/AT1R 的作用，从而对治疗心肌梗死后心律失常的相关分子机制有了新的认识，同时也将推动干细胞移植在心肌梗死治疗中的临床应用进程。