转录因子AP-2α在缺血诱导心肌血管新生中的作用及机制

Fibroblast Growth Factor 2 (FGF2) binds to its receptor to activate β-arrestin2/Akt signaling pathway, which promotes the angiogenesis. However, the molecular mechanism of β-arrestin2 regulation remains unknown. Our previous studies have indicated that upregulation of AMP-activated protein kinase (AMPK) activated transcriptional factor AP-2α and gene knockout of AMPK delayed the angiogenesis in ischemic hindlimb. Our exciting preliminary data also showed that AP-2α can bind to the DNA in β-arrestin2 gene promoter by analysis of bioinformatics and ChIPs. Knockout of FGF2 attenuated the angiogenesis and the recovery of cardiac function after myocardium infarction in Apoe-/- mice. Therefore, we hypothesized that AMPK via activation of AP-2α upregulates β-arrestin2 gene expression, leading to the accelerated angiogenesis and improved heart function in ischemic heart. In order to testify this hypothesis, comprehensive experimental approaches, including cellular and molecular biological, physiological and pharmacological means, will be used (1) to identity AP-2α as a new transactional factor of β-arrestin2 gene, (2) to investigate whether upregulation of AP-2α-dependent β-arrestin2 gene expression promotes migration, proliferation and tube formation in cultured vascular endothelial cells, (3) to determine the role of AP-2α in angiogenesis and recovery of heart function in mice following myocardium infarction. This powerful combination of in vitro and in vivo techniques and gain/loss-of-function approaches will yield important insights into how AMPK activation via AP-2α/β-arrestin2 enhances the angiogenesis in ischemic heart and improves cardiac function.

成纤维细胞生长因子2（FGF2）通过其受体激活β-arrestin2/Akt信号通路，促进血管新生，但相关机制不明。既往研究发现激活AMP活化的蛋白激酶（AMPK）能增加转录因子AP-2α的活性和促进血管新生。预实验发现AP-2α能与β-arrestin2的基因启动子DNA结合；敲除FGF2延缓了缺血心脏心功能的恢复。据此，我们假设“AMPK可能通过上调AP-2α依赖的β-arrestin2基因转录而促进缺血心肌的血管新生，进而改善心功能”。本课题拟用多种先进的生物学实验方法，体外体内研究相结合，验证AP-2α是β-arrestin2的转录因子，探讨AP-2α对β-arrestin2基因转录的调节作用是否促进了内皮细胞增殖、迁移及形成小管等能力，在小鼠心肌缺血模型确立AP-2α在缺血心肌血管新生中的作用。本研究旨在发现缺血心肌血管新生的新机制，从而为开发改善心肌缺血药物提供新的分子靶点。

成纤维细胞生长因子2（FGF2）通过其受体激活β-arrestin2/Akt信号通路，促进血管新生，但相关机制不明。既往研究发现激活AMP活化的蛋白激酶（AMPK）能增加转录因子AP-2α的活性和促进血管新生。预实验发现AP-2α能与β-arrestin2的基因启动子DNA结合；敲除FGF2延缓了缺血心脏心功能的恢复。据此，我们假设“AMPK可能通过上调AP-2α依赖的β-arrestin2基因转录而促进缺血心肌的血管新生，进而改善心功能”。本课题拟用多种先进的生物学实验方法，体外体内研究相结合，验证AP-2α是β-arrestin2的转录因子，探讨AP-2α对β-arrestin2基因转录的调节作用是否促进了内皮细胞增殖、迁移及形成小管等能力，在小鼠心肌缺血模型确立AP-2α在缺血心肌血管新生中的作用。本研究旨在发现缺血心肌血管新生的新机制，从而为开发改善心肌缺血药物提供新的分子靶点.