title: High concentrations of uric acid inhibit angiogenesis via regulation of the Krüppel-like factor 2-vascular endothelial growth factor-A axis by miR-92a.
abstract: BACKGROUND
  Angiogenesis is a critical component of many pathological conditions, and microRNAs (miRNAs) are indispensable in angiogenesis. It is unclear whether miRNAs regulate angiogenesis in the presence of high concentrations of uric acid (HUA), and the underlying mechanisms remain unknown.
  
  
  RESULTS
  It was found that HUA inhibited the angiogenic ability of endothelial cells. miRNA expression profiling was conducted using microarray assays in HUA-stimulated endothelial cells. Eighteen differentially expressed miRNAs were subjected to bioinformatic analyses. The results indicated that miR-92a was negatively regulated and was closely related to angiogenesis. Furthermore, the effects of miR-92a on HUA-stimulated endothelial cell angiogenesis and the underlying mechanisms were investigated in dual-luciferase reporter assays, electrophoretic mobility shift assays, immunoblot assays, and tube formation assays. It was determined that Krüppel-like factor 2 (KLF2) is a target gene of miR-92a, and KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. miR-92a and VEGFA overexpression or KLF2 downregulation alleviates the HUA-mediated inhibition of angiogenesis in endothelial cells in vitro.
  
  
  CONCLUSIONS
  This study reported that there is a novel pathway regulating angiogenesis under HUA conditions. In the presence of HUA, miR-92a downregulation increased KLF2 expression, subsequently inhibiting VEGFA, which resulted in decreased angiogenesis. Thus, this study reports a possible mechanism for cardiovascular injury caused by hyperuricemia and suggests that the miR-92a-KLF2-VEGFA axis may be a target for hyperuricemia treatment.
authors: State Key Laboratory of Kidney Diseases, Department of Nephrology, Chinese PLA Institute of Nephrology, National Clinical Research Center for Kidney Disease, Chinese PLA General Hospital.
authors: Shandong
authors: S
authors: Yu
authors: Quan
authors: Q
authors: Hong
authors: Yuanda
authors: Y
authors: Wang
authors: Kai
authors: K
authors: Hou
authors: Liyuan
authors: L
authors: Wang
authors: Yang
authors: Y
authors: Zhang
authors: Bo
authors: B
authors: Fu
authors: Yunan
authors: Y
authors: Zhou
authors: Wei
authors: W
authors: Zheng
authors: Xiangmei
authors: X
authors: Chen
authors: Di
authors: D
authors: Wu
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001665:Binding Sites; D016022:Case-Control Studies; D002478:Cells, Cultured; D019295:Computational Biology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014527:Uric Acid / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014527:Uric Acid