title: Transforming growth factor-beta1 induces apoptosis in vascular endothelial cells by activation of mitogen-activated protein kinase.
abstract: BACKGROUND
  Vascular endothelial cell apoptosis is central in atherosclerosis and intimal hyperplasia. Transforming growth factor (TGF)-beta1 induces endothelial cell apoptosis through unidentified mechanism(s). Although TGF-beta1 signals through the Smad proteins, in some nonendothelial cell types it also activates the mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAPK [p38(MAPK)]). p38(MAPK) relays apoptotic signals in several cell types. We hypothesized that TGF-beta1 activates endothelial cell MAPKs and induces apoptosis through p38(MAPK) activation.
  
  
  METHODS
  Human umbilical vein or bovine capillary endothelial cells were incubated with TGF-beta1 for 0.5 to 12 hours. MAPK activation was characterized by Western blotting with antibodies to phosphorylated extracellular signal-regulated kinase 1/2, p38(MAPK), or c-Jun N-terminal kinases 1/2. To study apoptosis, extracts of cells incubated with TGF-beta1 for 6 hours with or without MAPK inhibitors were characterized by Western blotting analysis of poly (ADP-Ribose) polymerase degradation.
  
  
  RESULTS
  TGF-beta1 induced p38(MAPK), extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase 1/2 activation and increased apoptosis. Inhibition of p38(MAPK) significantly reduced TGF-beta1-induced apoptosis. In contrast, inhibition of other signaling pathways was ineffective.
  
  
  CONCLUSIONS
  TGF-beta1 induces endothelial cell apoptosis through p38(MAPK) activation. Because TGF-beta1 is upregulated in vascular remodeling, p38(MAPK) is a potential target to prevent endothelial cell apoptosis during this process.
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, The Seymour Cohn Cardiovascular Surgery Research Laboratory, New York University School of Medicine, New York 10016, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Hyman
authors.forename: Graziano
authors.initials: G
authors.lastname: Seghezzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pintucci
authors.forename: Giulia
authors.initials: G
authors.lastname: Stellari
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Grossi
authors.forename: Aubrey C
authors.initials: AC
authors.lastname: Galloway
authors.forename: Paolo
authors.initials: P
authors.lastname: Mignatti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases