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ABSTRACT: Congenital heart disease is the commonest human birth defect occurring in 1% of the population worldwide, whereas acquired heart disease is the main cause of mortality in the elderly western populations, highlighting the importance of research focus on signaling pathways involved in cardiac development and disease. Notch signaling pathway is important for cell-cell communication that controls tissue formation and homeostasis during embryonic and adult life, but the precise cell targets of Notch signaling in the mammalian heart remain poorly defined. Here, we report that conditional over-expression of Notch1 intracellular domain (NICD1) in the embryonic cardiomyocyte compartment results in developmental defects and perinatal lethality in mice. In contrast, augmentation of endogenous Notch reactivation after myocardial infarction in the adult by intramyocardial delivery of a Notch1 pseudoligand increases survival rate improves cardiac functional performance and minimizes fibrosis, promoting proliferative and angiogenic mechanisms. These results reveal a strict requirement for cell-autonomous modulation of Notch signaling during heart morphogenesis, and illustrate how the same signaling pathway that promotes congenital heart defects when perturbed in the embryo can be therapeutically redeployed for the treatment of adult myocardial damage. Additionally, we sought to determine the role of NF-κB pathway in the adult myocardium and acquired cardiac disease. Insight into the function of nuclear factor κB (NF-κB) in the adult heart has been hampered by the embryonic lethality of constitutive NF-κB inactivation in mice. Using Cre/loxP technology, we disrupted in a cardiac-specific manner the NF-κB essential modulator (NEMO) in the murine heart, which simulated the adaptive changes underlying human heart failure, causing adultonset dilated cardiomyopathy accompanied by inflammation and apoptosis. Pressure overload challenges of NF-κB-deficient young hearts precociously induced the functional decrements that develop spontaneously in older knockout animals. Oxidative stress in NF-κB-deficient cardiomyocytes is a critical pathological component that can be attenuated with antioxidant diet in vivo. These results reveal an essential physiological role for NF-κB in the adult heart to maintain cardiac function in response to aging-related or mechanical challenges, in part through modulation of oxidative stress. Taken together, our observations provide valuable insights regarding the cardiomyocyteautonomous role of Notch1 and NEMO/ NF-κB signaling in congenital and acquired heart disease.