Antioxidant Amelioration of Dilated Cardiomyopathy Caused by Conditional Deletion of NEMO/IKKγ in Cardiomyocytes

Rationale: Insight into the function of nuclear factor (NF)-kappa B in the adult heart has been hampered by the embryonic lethality of constitutive NF-kappa B inactivation. Objective: The goal of the present study was therefore to gain insights into the role of NF-kappa B pathway specifically in mouse cardiomyocytes by conditional deletion of the NF-kappa B essential modulator (NEMO). Methods and Results: Using a Cre/loxP system, we disrupted the Nemo gene in a cardiomyocyte-specific manner in the heart, which simulated gene expression changes underlying human heart failure and caused adult-onset dilated cardiomyopathy accompanied by inflammation and apoptosis. Pressure overload challenges of NEMO-deficient young hearts precociously induced the functional decrements that develop spontaneously in older knockout animals. Moreover, oxidative stress in NEMO-deficient cardiomyocytes is a critical pathological component that can be attenuated with antioxidant diet in vivo. Conclusions: These results reveal an essential physiological role for NEMO-mediated signaling in the adult heart to maintain cardiac function in response to age-related or mechanical challenges, in part through modulation of oxidative stress. (Circ Res. 2010;106:133-144.)