Sangwung Panjamaporn, Zhou Guangjin, Lu Yuan, Liao Xudong, Wang Benlian, Mutchler Stephanie M, Miller Megan, Chance Mark R, Straub Adam C, Jain Mukesh K
1 Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
2 Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Vasc Med. 2017 Oct;22(5):363-369. doi: 10.1177/1358863X17722211. Epub 2017 Aug 19.
Hemoglobin subunit alpha (HBA) expression in endothelial cells (ECs) has recently been shown to control vascular tone and function. We sought to elucidate the transcriptional regulation of HBA expression in the EC. Gain of KLF2 or KLF4 function studies led to significant induction of HBA in ECs. An opposite effect was observed in ECs isolated from animals with endothelial-specific ablation of Klf2, Klf4 or both. Promoter reporter assays demonstrated that KLF2/KLF4 transactivated the hemoglobin alpha promoter, an effect that was abrogated following mutation of all four putative KLF-binding sites. Fine promoter mutational studies localized three out of four KLF-binding sites (sites 2, 3, and 4) as critical for the transactivation of the HBA promoter by KLF2/KLF4. Chromatin immunoprecipitation studies showed that KLF4 bound to the HBA promoter in ECs. Thus, KLF2 and KLF4 serve as important regulators that promote HBA expression in the endothelium.
最近研究表明，内皮细胞（ECs）中血红蛋白α亚基（HBA）的表达可调控血管张力和功能。我们试图阐明ECs中HBA表达的转录调控机制。KLF2或KLF4功能增强研究导致ECs中HBA显著诱导。在从Klf2、Klf4或两者内皮特异性缺失的动物中分离出的ECs中观察到相反的效果。启动子报告基因检测表明，KLF2/KLF4可反式激活血红蛋白α启动子，在所有四个假定的KLF结合位点发生突变后，这种效应被消除。精细的启动子突变研究将四个KLF结合位点中的三个（位点2、3和4）定位为KLF2/KLF4反式激活HBA启动子的关键位点。染色质免疫沉淀研究表明，KLF4在ECs中与HBA启动子结合。因此，KLF2和KLF4是促进内皮细胞中HBA表达的重要调节因子。
