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Impaired Notch4 activity elicits endothelial cell activation and apoptosis: implication for transplant arteriosclerosis.

AbstractOBJECTIVE:
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.
METHODS AND 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.
AuthorsT Quillard, S Coupel, F Coulon, J Fitau, M Chatelais, M C Cuturi, E Chiffoleau, B Charreau
JournalArteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 28 Issue 12 Pg. 2258-65 (Dec 2008) ISSN: 1524-4636 [Electronic] United States
PMID18802018 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Basic Helix-Loop-Helix Transcription Factors
  • Cytokines
  • Homeodomain Proteins
  • Inflammation Mediators
  • NOTCH4 protein, human
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptor, Notch4
  • Receptors, Notch
  • Transcription Factor HES-1
  • HES1 protein, human
Topics
  • Animals
  • Apoptosis (physiology)
  • Basic Helix-Loop-Helix Transcription Factors (antagonists & inhibitors, genetics, physiology)
  • Cells, Cultured
  • Coronary Artery Disease (etiology, pathology, physiopathology)
  • Cytokines (metabolism, pharmacology)
  • Down-Regulation
  • Endothelial Cells (pathology, physiology)
  • Gene Silencing
  • Heart Transplantation (adverse effects, pathology, physiology)
  • Homeodomain Proteins (antagonists & inhibitors, genetics, physiology)
  • Humans
  • Inflammation Mediators (metabolism, pharmacology)
  • Proto-Oncogene Proteins (antagonists & inhibitors, genetics, physiology)
  • RNA, Messenger (genetics, metabolism)
  • RNA, Small Interfering (genetics)
  • Rats
  • Rats, Inbred Lew
  • Receptor, Notch4
  • Receptors, Notch (antagonists & inhibitors, genetics, physiology)
  • Signal Transduction
  • Transcription Factor HES-1
  • Transplantation, Homologous

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