基于气血理论和TGF-β1/Smad3/ROS/miRNA-200a信号通路探讨放射性心肌纤维化发生机制及当归红芪超滤物的防治效应

Heart failure is a serious stage of cardiovascular disease and the main cause of death. Myocardial fibrosis is an important pathological basis of chronic heart failure. Radiation-induced myocardial fibrosis（RIMF） is a common pathological change in radiation-induced heart disease. Based on pathological mechanisms that radiation can directly or indirectly promote ROS generation, activate inflammatory cells and cytokines, promote fibroblast proliferation and increase myocardial fibrosis, Combined with the theoretical background and previous research results TGF-β1/Smad3/ROS/miRNA-200a activation can protect myocardial cell injury, Guided by the“Qi- Xue”theory , we here hypothesis that “the ultra-filtration extracted of Angelica Sinensis and Hedysarum Polybotrys protect RIMF by inhibiting the TGF-β1/Smad3/ROS signaling pathway and up-regulating miRNA-200a expression”. The relationship between TGF-β1/Smad3/ROS and miRNA-200a in RIMF was detected and target gene and signal pathways of miRNA-200a downstream were found by using transgenic rats，in situ hybridization and gene chip, mechanisms of the ultra-filtration extracted of Angelica Sinensis and Hedysarum Polybotrys intervention RIMF was clarified to provide a theoretical basis for RIMF.

心衰是心血管疾病的严重阶段及主要死因，心肌纤维化是慢性心衰重要病理基础，放射性心肌纤维化是放射性心脏损害的主要病理变化。本课题基于辐射能够促进ROS生成，激活炎症细胞和细胞因子，促进成纤维细胞增殖并加重心肌纤维化的病理机制，并结合TGF-β1/Smad3/ROS/miRNA-200a信号通路活化可保护心肌细胞损伤的理论背景，在中医气血理论指导下，根据前期研究结果提出“当归红芪超滤物可能通过抑制TGF-β1/Smad3/ROS信号通路，上调miRNA-200a表达干预放射性心肌纤维化”的工作假说，采用转基因大鼠、原位杂交、基因芯片等技术检测放射性心肌纤维化组织中TGF-β1/Smad3/ROS及miRNA-200a之间的关系，寻找miRNA-200a下游靶基因及信号通路，阐明当归红芪超滤物干预放射性心肌纤维化的作用机制，为临床应用当归红芪超滤物防治放射性心肌损害及心肌纤维化提供理论依据。

放射性心肌纤维化是胸部肿瘤放射治疗引起心脏迟发性损伤的主要病理变化，TGF-β1/Smad3/ROS/miRNA-200a信号通路介导心肌纤维化的发生起到关键作用。本项目以中医“气血”理论为指导，基于前期研究结果提出具有“益气活血”功效的当归红芪超滤物治疗放射性心肌纤维化的分子生物学内涵是“通过抑制TGF-β1/Smad3/ROS/miRNA-200a信号通路来抑制心肌成纤维细胞增殖和氧化损伤，以保护放射性心肌纤维化”的假说。本项目采用基因沉默、转染、芯片检测等技术研究TGF-β1/Smad3/ROS/miRNA-200a信号通路与心肌成纤维细胞各表型之间的关系，阐明当归红芪超滤物保护放射性心肌纤维化的作用机制。本项目将对防治放射性心肌纤维化及提高肿瘤治疗疗效具有重要意义。