title: Signal transducers and activators of transcription 3 mediates up-regulation of angiotensin II-induced tissue inhibitor of metalloproteinase-1 expression in cultured human senescent fibroblasts.
abstract: BACKGROUND
  Angiotensin II (Ang II), a principal effector of renin-angiotensin system (RAS) and increased in aging tissues, can stimulate JAK/STAT pathway via the G-protein-coupled Ang II receptor type I (AT1) and induce nuclear translocation of signal transducers and activators of transcription (STAT). To further explore the role of Ang II in aging, we examined the effect of Ang II on human replicative senescent diploid fibroblast WI-38 cells.
  
  
  METHODS
  Human senescent WI-38 cells were incubated with Ang II, receptor antagonist PD123319, valsartan, STAT3 sense plasmid, and/or STAT3 antisense plasmids. Methods were applied including electrophoretic mobility shift assay (EMSA), Western blot, transfection, and laser scanning confocal microscopy.
  
  
  RESULTS
  It was found that cultured human senescent WI-38 cells constitutively expressed tissue inhibitor of metalloproteinase-1 (TIMP-1), and Ang II induced TIMP-1 protein expression in both time- and dose-dependent manners. Ang II induced STAT-DNA binding activity also in both time- and dose-dependent manners. And supershift assay showed that the sis-inducing factor (SIF) band contained STAT3 proteins. STAT3 antisense oligonucleotides could inhibit both Ang II-induced STAT3-DNA binding activity as well as TIMP-1 expression.
  
  
  CONCLUSIONS
  Ang II could up-regulate TIMP-1 expression through activating STAT3 signal pathway in human senescent cells, indicating that Ang II-STAT3-TIMP-1 pathway may be involved in the mechanism of sclerosis in aging tissues.
authors.affiliation: Department of Nephrology, General Hospital of People's Liberation Army, Beijing 100853, China.
authors.forename: Xiao-dan
authors.initials: XD
authors.lastname: Wang
authors.forename: Xiang-mei
authors.initials: XM
authors.lastname: Chen
authors.forename: Jian-zhong
authors.initials: JZ
authors.lastname: Wang
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.forename: Zhe
authors.initials: Z
authors.lastname: Feng
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Feng-yang
authors.initials: FY
authors.lastname: Wang
authors.forename: Dai-ming
authors.initials: DM
authors.lastname: Fan
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D002478:Cells, Cultured; D016922:Cellular Senescence; D004247:DNA / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D050796:STAT3 Transcription Factor / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D000804:Angiotensin II; D004247:DNA