RGD Reference Report - Impaired Notch4 activity elicits endothelial cell activation and apoptosis: implication for transplant arteriosclerosis. - Rat Genome Database

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

Authors: Quillard, T  Coupel, S  Coulon, F  Fitau, J  Chatelais, M  Cuturi, MC  Chiffoleau, E  Charreau, B 
Citation: Quillard T, etal., Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2258-65. Epub 2008 Sep 18.
RGD ID: 6480862
Pubmed: PMID:18802018   (View Abstract at PubMed)
DOI: DOI:10.1161/ATVBAHA.108.174995   (Journal Full-text)

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. 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
arteriosclerosis  IEP 6480862 RGD 
arteriosclerosis  ISONOTCH4 (Homo sapiens)6480862; 6480862 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Notch4  (notch receptor 4)

Genes (Mus musculus)
Notch4  (notch 4)

Genes (Homo sapiens)
NOTCH4  (notch receptor 4)


Additional Information