title: Canonical Wnt/β-catenin signaling in epicardial fibrosis of failed pediatric heart allografts with diastolic dysfunction.
abstract: BACKGROUND
  Failed pediatric heart allografts with diastolic dysfunction exhibit severe epicardial fibrosis. The molecular mechanism underlying this process is poorly understood. Canonical Wnt/β-catenin signaling plays an important role in epithelial-mesenchymal transition and is implicated in fibrosing diseases. In this study, we tested the hypothesis that canonical Wnt/β-catenin signaling is activated in epicardial fibrosis of end-stage dysfunctional pediatric allografts.
  
  
  METHODS
  Fourteen explanted heart grafts of 12 patients who had undergone 14 heart transplantations were used for immunohistochemical staining of β-catenin and its nuclear binding partners, T-cell factor/lymphoid enhancer factor family transcriptional factors. Fourteen age-matched native hearts from patients who had undergone first heart transplantation without evidence of epicardial fibrosis were used as controls.
  
  
  CONCLUSIONS
  Epicardial fibroblasts from explanted allografts demonstrated nuclear accumulation of β-catenin. These cells also showed nuclear positivity for T-cell factor 4. No T-cell factor 3 expression was present in the epicardium. T-cell factor 1 and lymphoid enhancer factor 1 were observed in lymphocytes, but not in other cell types of the epicardium. These findings suggest an association between canonical Wnt/beta-catenin signaling and epicardial fibrosis of failed pediatric heart allografts. Should activation of this pathway be shown to be causal to epicardial fibrosis in this setting, then inhibition of this pathway may help to prevent this devastating process.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Ye
authors.forename: Yao
authors.initials: Y
authors.lastname: Ge
authors.forename: Gregory
authors.initials: G
authors.lastname: Perens
authors.forename: Longsheng
authors.initials: L
authors.lastname: Hong
authors.forename: Haodong
authors.initials: H
authors.lastname: Xu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: Faqian
authors.initials: F
authors.lastname: Li
mesh_terms: D016022:Case-Control Studies; D003971:Diastole; D005347:Fibroblasts / Q000737:chemistry / Q000473:pathology; D005355:Fibrosis; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007150:Immunohistochemistry; D010496:Pericardium / Q000737:chemistry* / Q000473:pathology; D058118:Transcription Factor 7-Like 2 Protein / Q000032:analysis; D017211:Treatment Failure; D018754:Ventricular Dysfunction / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016276:Ventricular Function; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000032:analysis*
chemical_list: C495270:CTNNB1 protein, human; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin