title: PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells.
abstract: OBJECTIVE
  Pigment epithelial-derived factor (PEDF) is a potent anti-angiogenic factor whose effects are partially mediated through the induction of endothelial cell apoptosis. The pathway mediating endothelial cell apoptosis has not been fully established. Here we investigated the participation of peroxisome proliferator-activated receptor gamma (PPARgamma) and p53 in the apoptosis of human umbilical vein endothelial cells (HUVECs).
  
  
  RESULTS
  HUVECs pretreated with either PPARgamma antagonist or PPARgamma small interfering RNA (siRNA) suppressed PEDF-induced apoptosis as determined by TUNEL assay, annexin V-FITC/PI staining, and cleavage of procaspase-8, -9, -3. PEDF sequentially induced PPARgamma and p53 expression as observed in immunoblotting and immunofluoresence assays. PEDF also increased the transcriptional activity of PPARgamma as evident from electromobility shift assays, and p53 as determined by the phosphorylation and acetylation of p53 and the induction of Bax. The induction of p53 by PEDF was abolished by either PPARgamma antagonist or PPARgamma siRNA. PEDF-mediated HUVEC apoptosis and cleavage of procaspases were significantly attenuated by p53 siRNA.
  
  
  CONCLUSIONS
  Our observations indicate that PEDF induces HUVECs apoptosis through the sequential induction of PPARgamma and p53 overexpression. With the growing interest in anti-angiogenesis as a novel approach to cancer therapy, defining the mechanism of PEDF-mediated HUVEC apoptosis may facilitate the development of new therapeutics.
authors.affiliation: Departments of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: T-C
authors.initials: TC
authors.lastname: Ho
authors.forename: S-L
authors.initials: SL
authors.lastname: Chen
authors.forename: Y-C
authors.initials: YC
authors.lastname: Yang
authors.forename: C-L
authors.initials: CL
authors.lastname: Liao
authors.forename: H-C
authors.initials: HC
authors.lastname: Cheng
authors.forename: Y-P
authors.initials: YP
authors.lastname: Tsao
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D005136:Eye Proteins / Q000502:physiology*; D006801:Humans; D009414:Nerve Growth Factors / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*; D015843:Serpins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014471:Umbilical Veins / Q000166:cytology; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D020169:Caspases; D005136:Eye Proteins; D009414:Nerve Growth Factors; D047495:PPAR gamma; D015843:Serpins; D016159:Tumor Suppressor Protein p53; D000099174:Pigment Epithelium-Derived Factor