转录因子Ets-1调控血管生成及心肌再生参与心肌梗死后心肌重构的作用及机制研究

The pathologenesis of myocardial infaction induced cardiac remodeling is a complex process, which is still unclear. Angiogenesis in infarct myocardium is important to rescue the viable myocardial. Nuclear transcription factors ETS-1 play a critial role in the angiogenesis process, including degradation of the basement membrane, endothelial cell migration and capillary tube formation. Our pre-experiment showed that the level of ETS-1 expression was higher in the border area of infarct than in distant area. We also found that overexpression of ETS-1 gene could increase the capillary as well as arteriolar density and myocardial cell regeneration, and improve the cardiac remodeling and dysfunction induced by myocardial infarction. In our study, animal and celluar experiments will be processed in this project. According to these findings, it may be speculated that hypoxia could induced the activation of ETS-1 in the border area of infarcted myocardium, and the activation of ETS-1 enhanced the expression of CXCR4 and the internalization and recyling of αvβ3 between cell membrane and plasm, that all contributed to the directed migration of endothelial cells to the infarct region. A series of advanced technologies will be undertaken. This project will provide a new theoretical support in understanding the pathological mechanism of myocardial infarction-induced ETS-1 mediated angiogenesis, which may be helpful to provide a novel target for drug discovery and therapeutic inervention of myocardial infartion

血管生成和心肌再生对于心肌梗死后的心肌重构和心功能改善有着重大意义。内皮细胞中核转录因子ETS-1在血管新生过程中发挥重要作用。我们前期实验表明：心梗周围区ETS-1的表达水平较远区明显增加，而过表达ETS-1基因可增加心肌组织中的血管生成及心肌干细胞再生，并且可显著改善心梗后心脏结构及功能的改变。我们认为，缺氧可诱导心梗周围区域中ETS-1的表达及活化，一方面活化的ETS-1可通过调控SDF-1/CXCR4生物轴及整合素αvβ3内吞胞吐循环，促进内皮细胞向梗死区组织进行定向迁移，促进血管再生；另一方面活化的ETS-1可促进心肌干细胞的再生，二者共同作用，最终促进心梗后的心肌存活和心脏功能的改善。本研究拟以心肌梗死小鼠为动物模型，通过体内及体外实验，深入研究ETS-1在心肌梗死后修复中的作用及具体分子机制，从而为以ETS-1为靶点对心肌梗死进行靶向治疗提供重要的理论依据。

心肌梗死及其相关并发症是威胁人类健康的主要疾病之一。心肌梗死后心肌细胞大量丢失，心肌被瘢痕组织所致代替，导致心室大小、结构、形态以及心脏功能变化，是心肌梗死后心功能恶化的病理基础，主要表现为心肌梗死区膨出，非梗死区心肌肥大、室壁增厚、心肌间质纤维化，最终导致整个心室进行性扩张、心脏收缩功能减低。心肌梗死后的血管再生对存活心肌以及心功能的恢复有着重大意义。这一过程涉及多种蛋白分子和转录因子共同作用，但其具体发生机制仍不明确。内皮细胞中核转录因子ETS-1的表达在血管新生的起始、重塑及与邻近血管连接时发挥重要作用。我们的预实验结果显示：心肌梗死周围区ETS-1的表达水平较远区明显增加，并且过表达ETS-1基因能够通过增加心肌组织中血管生成改善心肌梗死后心脏结构及功能的改变。本课题项目以心肌梗死小鼠为动物模型，通过多层次实验，分别在体内及体外实验中深入研究ETS-1调控心肌梗死后心功能修复的具体分子机制，首次阐明发现缺氧可诱导心肌梗死周围区域中ETS-1的活化，活化的ETS-1通过调控SDF-1/CXCR4轴及整合素αvβ3的表达，促进内皮细胞向梗死区域组织进行定向迁移，促进梗死周围组织血管生成，进而改善心肌梗死后心功能，为以ETS-1为靶点对心肌梗死进行靶向治疗提供重要理论依据。