Inhibition of notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart.
Circ Res
; 107(3): 429-41, 2010 Aug 06.
Article
en En
| MEDLINE
| ID: mdl-20558824
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 ANDRESULTS:
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 gamma-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. After cessation of Notch blockade and recovery of myocyte regeneration, cardiac anatomy and function were largely restored.CONCLUSIONS:
Notch1 signaling is a critical determinant of CSC growth and differentiation; when this cascade of events is altered, cardiomyogenesis is impaired, physiological cardiac hypertrophy is prevented, and a life-threatening myopathy supervenes.
Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Cardiomiopatía Dilatada
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Miocitos Cardíacos
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Receptor Notch1
Límite:
Animals
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Humans
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Newborn
Idioma:
En
Revista:
Circ Res
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos