title: Transcriptional regulation of Bim by FOXO3a and Akt mediates scleroderma serum-induced apoptosis in endothelial progenitor cells.
abstract: BACKGROUND
  Endothelial progenitor cells (EPCs) contribute to vascular regeneration/repair and thus may protect against scleroderma vasculopathy. We aimed to determine whether circulating EPCs were reduced in scleroderma, whether scleroderma sera could induce EPC apoptosis, and, if so, what the underlying apoptotic signaling pathway was.
  
  
  RESULTS
  Circulating EPC levels were quantified in 54 patients with scleroderma and 18 healthy control subjects by colony-forming unit assay and flow cytometry, which revealed markedly decreased EPC levels in scleroderma patients relative to healthy subjects. Substantial apoptosis was detected in EPCs after culturing in the presence of scleroderma sera compared with normal sera. Intriguingly, depletion of the IgG fraction from scleroderma sera completely abolished the apoptotic effects. Furthermore, scleroderma sera inhibited the activation/phosphorylation of Akt, which in turn suppressed the phosphorylation and degradation of forkhead transcription factor FKHRL1 (FOXO3a), resulting in the upregulation of apoptotic protein Bim. siRNA-mediated FOXO3a and Bim knockdown substantially reduced scleroderma serum-induced EPC apoptosis. Importantly, Bim expression and baseline apoptosis were increased in EPCs freshly isolated from scleroderma patients relative to that obtained from healthy subjects.
  
  
  CONCLUSIONS
  Scleroderma serum-induced EPC apoptosis is mediated chiefly by the Akt-FOXO3a-Bim pathway, which may account, at least in part, for the decreased circulating EPC levels in scleroderma patients.
authors.affiliation: Department of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Shoukang
authors.initials: S
authors.lastname: Zhu
authors.forename: Sarah
authors.initials: S
authors.lastname: Evans
authors.forename: Bin
authors.initials: B
authors.lastname: Yan
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Povsic
authors.forename: Victor
authors.initials: V
authors.lastname: Tapson
authors.forename: Pascal J
authors.initials: PJ
authors.lastname: Goldschmidt-Clermont
authors.forename: Chunming
authors.initials: C
authors.lastname: Dong
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D000072224:Bcl-2-Like Protein 11; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay / Q000379:methods; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012038:Regeneration; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D044967:Serum / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007074:Immunoglobulin G; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt