Inhibition of Notch1-Dependent Cardiomyogenesis Leads to a Dilated Myopathy in the Neonatal Heart

Abstract

Rationale: Physiological hypertrophy in the developing heart has been considered the product of an increase in volume of preexisting fetal cardiomyocytes in the absence of myocyte formation. Objective: In this study, we tested whether the mouse heart at birth has a pool of cardiac stem cells (CSCs) that differentiate into myocytes contributing to the postnatal expansion of the parenchymal cell compartment. Methods and Results: We have found that the newborn heart contains a population of c-kit-positive CSCs that are lineage negative, self-renewing, and multipotent. CSCs express the Notch1 receptor and show the nuclear localization of its active fragment, N1ICD. In 60% of cases, N1ICD was coupled with the presence of Nkx2.5, indicating that the commitment of CSCs to the myocyte lineage is regulated by Notch1. Importantly, overexpression of N1ICD in neonatal CSCs significantly expanded the proportion of transit-amplifying myocytes.To establish whether these in vitro findings had a functional counterpart in vivo, the Notch pathway was blocked in newborn mice by administration of a ␥-secretase inhibitor. This intervention resulted in the development of a dilated myopathy and high mortality rates. Ventricular decompensation was characterized by a 62% reduction in amplifying myocytes, which resulted in a 54% decrease in myocyte number. A t birth, the myocardium must accommodate the abrupt changes in the patterns of blood flow and circulatory resistance and the increasing demands of the rapidly growing organism. Physiological hypertrophy in the developing heart has been considered the result of an increase in volume of preexisting fetal cardiomyocytes, whereas the contribution of new myocytes to the postnatal expansion in ventricular mass was viewed as negligible at best. 1 However, the documentation of high levels of DNA synthesis in myocytes together with apoptotic cell death 2 indicate that the postnatal maturation of the heart is a complex process in which cardiomyogenesis may play a critical role in the acquisition of the adult heart phenotype.By viral tagging and clonal marking, we have shown that cardiomyogenesis in the adult mouse heart depends on the activation and differentiation of a pool of cardiac stem cells (CSCs) that express the c-kit antigen. 3 On the basis of these findings, the question can be raised whether primitive cells with similar properties are present in the neonatal heart and the generation of new myocytes is dictated by lineage commitment of these cells. According to the traditional model of growth in self-renewing organs, stem cells give rise to progenitorprecursor cells, which then become highly dividing amplifying cells that eventually reach terminal differentiation and growth arrest. 4 This hierarchically structured mechanism of parenchymal cell generation may account for the expansion in myocyte number and volume of the neonatal heart. CSC-derived amplifying myocytes replicate and concurrently differentiate, mimicking cellular hyperplasia and hypertrophy. 5 The possibility exists t...

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

“…Together, these results show that Notch-1 signaling is down-regulated in myocardium in early-stage DCM. 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).…”

“…Dilated cardiomyopathy, left ventricular noncompaction, cardiac development (36,40) VIP signaling map3k1(s915), ppp3cb(s469), plcg1(s1263), nfatc2(s136), prkar2b(s112), prkacb, prkar2a, prkar1a, nfkb1, ppp3ca…”

2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside protects murine hearts against ischemia/reperfusion injury by activating Notch1/Hes1 signaling and attenuating endoplasmic reticulum stress

“…When Notch signaling was blocked in newborn mice by the administration of DAPT, the mortality rate tended to increase. After DAPT cessation, cardiac function was largely restored [52] . Furthermore, a previous study showed that activation of Notch1 signaling in H9c2 cardiomyoblasts contributed to the cardioprotection provided by ischemic preconditioning and postconditioning [53] .…”

Insights Into Signaling in Cell-Based Therapy for Heart Disease

“…155 Accumulated evidence suggests that resident CSC recruitment and differentiation are mediated by Notch-mediated induction of reparative mechanisms in the damaged heart. [155][156][157][158] Urbanek et al 159 showed that pharmacological inhibition of Notch reduces the number of cycling c-kit+ CSCs and compromises their cardiac commitment. Moreover, inhibition of Notch signaling leads to severe dilated cardiomyopathy in newborn mice secondary to the reduced differentiation rate of cardiac progenitor cells.…”

“…Moreover, inhibition of Notch signaling leads to severe dilated cardiomyopathy in newborn mice secondary to the reduced differentiation rate of cardiac progenitor cells. 159 …”