title: Cleaved high molecular weight kininogen stimulates JNK/FOXO4/MnSOD pathway for induction of endothelial progenitor cell senescence.
abstract: OBJECTIVE
  Recently we have reported that cleaved high molecular weight kininogen (HKa) accelerates the onset of endothelial progenitor cells (EPCs) senescence by induction of reactive oxygen species (ROS). However, the mechanisms by which HKa induces production of ROS remain unknown. In this study, we have shown that HKa induces EPC senescence via stimulation of c-Jun N-terminal kinases (JNK)-related pathway.
  
  
  RESULTS
  Treatment of human EPCs with HKa for 72h stimulated JNK phosphorylation at Thr183/Tyr185, and FOXO4 phosphorylation at Thr451, Concomitantly, upregulated the expression of MnSOD at protein and mRNA levels in a concentration-dependent manner. HKa increased intracellular level of H2O2, without affecting the expression of catalase. To narrow down the functional domain of HKa, recombinant proteins of human HK heavy chain (HC, 19-380aa) and light chain (LC, 390-644aa) were generated. HC, but not LC, increased senescence of EPCs and intracellular ROS levels, to a similar extent with HKa. Moreover, HC at 50 nM increased FOXO4 phosphorylation at Thr451 and the protein level of MnSOD in EPCs.
  
  
  CONCLUSIONS
  These results demonstrate that HKa accelerates the onset of EPC senescence by stimulating JNK/FOXO4/MnSOD pathway, its effect is mediated by the HC.
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Xichen
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA. Electronic address: yiwu@temple.edu.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wu
mesh_terms: D001483:Base Sequence; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D016922:Cellular Senescence; D017931:DNA Primers; D004727:Endothelium / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D051858:Forkhead Transcription Factors; D006801:Humans; D007704:Kininogens / Q000737:chemistry / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008970:Molecular Weight; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D007704:Kininogens; D014157:Transcription Factors; D013482:Superoxide Dismutase; D048670:MAP Kinase Kinase 4
keywords: Endothelial progenitor cells; Kininogen; Reactive oxygen species; Senescence