Abstract 3434: The Role Of Notch Signaling In The Adult Myocardium: Control Of Myocyte Hypertrophy And Differentiation
Background. Notch signaling is essential during development and in homeostasis of several organ systems. Mutations in Notch genes cause cardiac malformations. However the role of this pathway in the adult heart has not been addressed.
Methods. We investigated Notch signaling in models of cardiac hypertrophy and failure. Notch activation was analyzed by immunostaining and quantitative RT-PCR. Cardiac response to stress was investigated in mice lacking Notch1 in the heart and in transgenics overexpressing Jagged1 in the myocardium.
Results. The wild-type heart responded to hemodynamic stress by an upregulation of the Notch ligand Jagged1 on cardiac myocytes and an activation of Notch1. Immunostaining showed that Notch1 activation occurred predominantly in cardiomyocytes. Nkx2.5- and GATA4-positive cardiac precursor cells also activated Notch. In cultured cardiomyocytes, Notch signaling interfered with terminal differentiation. In vitro, proliferating Nkx2.5-positive precursor cells displayed intense NIC staining. Under differentiation conditions, these cells downregulated the Notch pathway and produced cardiomyocytes. Pharmacological inhibition of the Notch pathway in vivo exacerbated cardiac hypertrophy and was detrimental to the adaptive response of the heart to stress. Similarly, mice with cardiac-specific deletion of Notch1 exhibited cardiac fibrosis, impaired cardiac function and decreased survival. To investigate the effects of chronic Notch activation in the heart, we generated transgenics with cardiac Jagged1 overexpression. A large proportion (40 –50%) of these mice demonstrated atrial enlargement, impairment of ventricular function, and die at 3 months of age.
Conclusions. Notch signaling is crucial for maintaining cardiac integrity in the adult mammalian heart. Activation of the Notch pathway relies on stimulated Jagged1 expression. In cardiomyocytes, Notch regulates the extent of the hypertrophic response and probably contributes to cell survival. In cardiac precursors, Notch controls cardiogenic differentiation. Importantly, both chronic inhibition and activation are detrimental to cardiac function, suggesting that fine tuning of Notch signaling in the heart is mandatory for proper cardiac homeostasis.