title: Impaired Notch4 activity elicits endothelial cell activation and apoptosis: implication for transplant arteriosclerosis.
abstract: OBJECTIVE
  Notch signaling pathway controls key functions in vascular and endothelial cells (EC). However, little is known about the role of Notch in allografted vessels during the development of transplant arteriosclerosis (TA). This study investigated regulation of the Notch pathway on cardiac allograft arteriosclerosis and further examined its implication in EC dysfunction.
  
  
  RESULTS
  Here we show that, among Notch receptors, Notch2, -3, and -4 transcript levels were markedly downregulated in TA compared to tolerant and syngeneic allografts. TA correlates with high levels of tumor necrosis factor (TNF), transforming growth factor (TGF)beta, and IL10, which consistently decrease Notch4 expression in transplants and cultured ECs. We found that inhibition of Notch activity, reflected by both a reduced CBF1 activity and Hes1 expression, parallels the downregulation of Notch4 expression mediated by TNF in ECs. Notch4 and Hes1 knockdown enhances vascular cell adhesion molecule-1 expression and promotes EC apoptosis. Silencing Notch4 or Hes1 also drastically inhibits repair of endothelial injury. Overall, our results suggest that Notch4 and basal Notch activity are required to maintain EC quiescence and for optimal survival and repair in response to injury.
  
  
  CONCLUSIONS
  Together, our findings indicate that impaired Notch4 activity in graft ECs is a key event associated with TA by triggering EC activation and apoptosis.
authors.affiliation: INSERM U643, Nantes, F44000 France.
authors.forename: T
authors.initials: T
authors.lastname: Quillard
authors.forename: S
authors.initials: S
authors.lastname: Coupel
authors.forename: F
authors.initials: F
authors.lastname: Coulon
authors.forename: J
authors.initials: J
authors.lastname: Fitau
authors.forename: M
authors.initials: M
authors.lastname: Chatelais
authors.forename: M C
authors.initials: MC
authors.lastname: Cuturi
authors.forename: E
authors.initials: E
authors.lastname: Chiffoleau
authors.forename: B
authors.initials: B
authors.lastname: Charreau
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D020868:Gene Silencing; D016027:Heart Transplantation / Q000009:adverse effects* / Q000473:pathology / Q000502:physiology; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014184:Transplantation, Homologous
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D018398:Homeodomain Proteins; D018836:Inflammation Mediators; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C106075:NOTCH4 protein, human; C078493:HES1 protein, human