Angiotensin II increases angiogenesis by NF-κB-mediated transcriptional activation of angiogenic factor AGGF1

  • FASEB J. 2018 Sep;32(9):5051-5062. doi: 10.1096/fj.201701543RR.
Wenxia Si  1  2 ,  Wen Xie  1 ,  Wenbing Deng  1 ,  Yi Xiao  3 ,  Sadashiva S Karnik  4  5  6  7 ,  Chengqi Xu  1 ,  Qiuyun Chen  4  5  6  7 ,  Qing Kenneth Wang  1  3  4  5  6  7  8
Affiliations
  • 1. Key Laboratory of Molecular Biophysics-Ministry of Education, Cardio-X Institute, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Huangshi Central Hospital-Edong Healthcare Group, Hubei Polytechnic University School of Medicine, Huangshi, China.
  • 3. College of Physics, Huazhong University of Science and Technology, Wuhan, China.
  • 4. Center for Cardiovascular Genetics, Cleveland Clinic, Cleveland, Ohio, USA.
  • 5. Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA; and.
  • 6. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
  • 7. Department of Molecular Medicine, Cleveland Clinic Learner College of Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; and.
  • 8. Department of Genetics and Genome Science, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
PMID: 29641288 DOI: 10.1096/fj.201701543RR
Abstract

Angiogenic factor with G-patch and FHA domains 1 (AGGF1) is involved in vascular development, angiogenesis, specification of hemangioblasts, and differentiation of veins. When mutated, however, it causes Klippel-Trenaunay syndrome, a vascular disorder. In this study, we show that angiotensin II (AngII)-the major effector of the renin-angiotensin system and one of the most important regulators of the cardiovascular system-induces the expression of AGGF1 through NF-κB, and that AGGF1 plays a key role in AngII-induced angiogenesis. AngII significantly up-regulated the levels of AGGF1 mRNA and protein in HUVECs at concentrations of 10-40 μg/ml but not >60 μg/ml. AngII type 1 receptor (AT1R) inhibitor losartan inhibited AngII-induced up-regulation of AGGF1, whereas AT2R inhibitor PD123319 further increased AngII-induced up-regulation of AGGF1. Up-regulation of AGGF1 by AngII was blocked by NF-κB inhibitors, and p65 binds directly to a binding site at the promoter/regulatory region of AGGF1 and transcriptionally activates AGGF1 expression. AngII-induced endothelial tube formation was blocked by small interfering RNAs (siRNAs) for RELA (RELA proto-oncogene, NF-κB subunit)/p65 or AGGF1, and the effect of RELA siRNA was rescued by AGGF1. AngII-induced angiogenesis from aortic rings was severely impaired in Aggf1+/- mice, and the effect was restored by AGGF1. These data suggest that AngII acts as a critical regulator of AGGF1 expression through NF-κB, and that AGGF1 plays a key role in AngII-induced angiogenesis.-Si, W., Xie, W., Deng, W., Xiao, Y., Karnik, S. S., Xu, C., Chen, Q., Wang, Q. K. Angiotensin II increases angiogenesis by NF-κB-mediated transcriptional activation of angiogenic factor AGGF1.

Keywords
AT1R; AT2R; p65.
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