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

Abstract

AimsNotch1 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 resultsIn 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.ConclusionsAltogether, 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.

Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

“…Our findings are consistent with previous reports of development of DCM in vitro and in newborn mice treated with an inhibitor of Notch-1-dependent signaling (36), or more pronounced cardiac dysfunction, fibrosis, and apoptosis in adult hearts from an agonist-induced hypertrophy model or Notch-1 cardiac-specific null mice (37). Similarly, transgenic mice overexpressing the Notch ligand JAGGED1 were protected from pressure overloadinduced cardiac hypertrophy (38).…”

“…Indeed, uncoupling of Notch-1 signaling in R9C (Fig. 4) suggests that Notch-1-activating compounds (i.e., activating antibodies, polypeptides, small molecules) may be clinically beneficial under DCM conditions, similar to that observed in hypertrophy (38) and potentially other pathological contexts.…”

Signaling Pathways in Cardiac Myocyte Apoptosis

“…In contrast to full length Jagged1, the cleaved Jagged1 intracellular domain (J1ICD) inhibits Notch signaling through binding with NICD and promoting its degradation [259]. Cardiac-specific J1ICD transgenic mice exhibited decreased Notch activity, alleviated cardiac hypertrophy, and apoptosis in response to pressure overload [260]. Whether the inhibition of apoptosis is a direct effect of J1ICD or a secondary response to reduced hypertrophy is not clear at this point.…”

3D bioprinted functional and contractile cardiac tissue constructs

“…Notch signaling plays an important role in heart development and regeneration [42–45]. Previous in vivo studies in Notch knock-out transgenic mice demonstrated that Notch inhibition diminished proliferation in neonatal cardiomyocytes and promoted maturation [46]. It is unclear whether in vitro Notch signaling regulates the formation of bioengineered cardiac tissues derived from neonatal heart cells.…”