Jagged1 intracellular domain-mediated inhibition of Notch1 signalling regulates cardiac homeostasis in the postnatal heart.

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Version: Final published version
Serval ID
serval:BIB_3EA71A9ACB28
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Jagged1 intracellular domain-mediated inhibition of Notch1 signalling regulates cardiac homeostasis in the postnatal heart.
Journal
Cardiovascular Research
Author(s)
Metrich M., Bezdek Pomey A., Berthonneche C., Sarre A., Nemir M., Pedrazzini T.
ISSN
1755-3245 (Electronic)
ISSN-L
0008-6363
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
108
Number
1
Pages
74-86
Language
english
Notes
Publication types: Journal ArticlePublication Status: ppublish
Abstract
AIMS: Notch1 signalling in the heart is mainly activated via expression of Jagged1 on the surface of cardiomyocytes. Notch controls cardiomyocyte proliferation and differentiation in the developing heart and regulates cardiac remodelling in the stressed adult heart. Besides canonical Notch receptor activation in signal-receiving cells, Notch ligands can also activate Notch receptor-independent responses in signal-sending cells via release of their intracellular domain. We evaluated therefore the importance of Jagged1 (J1) intracellular domain (ICD)-mediated pathways in the postnatal heart.
METHODS AND RESULTS: In cardiomyocytes, Jagged1 releases J1ICD, which then translocates into the nucleus and down-regulates Notch transcriptional activity. To study the importance of J1ICD in cardiac homeostasis, we generated transgenic mice expressing a tamoxifen-inducible form of J1ICD, specifically in cardiomyocytes. Using this model, we demonstrate that J1ICD-mediated Notch inhibition diminishes proliferation in the neonatal cardiomyocyte population and promotes maturation. In the neonatal heart, a response via Wnt and Akt pathway activation is elicited as an attempt to compensate for the deficit in cardiomyocyte number resulting from J1ICD activation. In the stressed adult heart, J1ICD activation results in a dramatic reduction of the number of Notch signalling cardiomyocytes, blunts the hypertrophic response, and reduces the number of apoptotic cardiomyocytes. Consistently, this occurs concomitantly with a significant down-regulation of the phosphorylation of the Akt effectors ribosomal S6 protein (S6) and eukaryotic initiation factor 4E binding protein1 (4EBP1) controlling protein synthesis.
CONCLUSIONS: Altogether, these data demonstrate the importance of J1ICD in the modulation of physiological and pathological hypertrophy, and reveal the existence of a novel pathway regulating cardiac homeostasis.
Keywords
Cardiac hypertrophy, Cardiomyocyte differentiation, Notch signalling, Jagged1-intracelullar domain
Pubmed
Web of science
Create date
09/11/2015 14:14
Last modification date
20/08/2019 13:35
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