Antioxidant amelioration of dilated cardiomyopathy caused by conditional deletion of NEMO/IKKgamma in cardiomyocytes.

Abstract

Insight into the function of nuclear factor (NF)-kappaB in the adult heart has been hampered by the embryonic lethality of constitutive NF-kappaB inactivation. The goal of the present study was therefore to gain insights into the role of NF-kappaB pathway specifically in mouse cardiomyocytes by conditional deletion of the NF-kappaB essential modulator (NEMO). 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. 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.