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


OBJECTIVE
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).


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.
European Molecular Biology Laboratory, Mouse Biology Unit, Campus A. Buzzati-Traverso, Rome, Italy.
P
P
Kratsios
M
M
Huth
L
L
Temmerman
E
E
Salimova
M
M
Al Banchaabouchi
A
A
Sgoifo
M
M
Manghi
K
K
Suzuki
N
N
Rosenthal
F
F
Mourkioti
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017353:Gene Deletion; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction
D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D051550:I-kappa B Kinase