Published online before print October 22, 2009, doi: 10.1161/CIRCRESAHA.109.202200
Submitted on June 4, 2009
Revised on September 30, 2009
Accepted on October 13, 2009
Antioxidant Amelioration of Dilated Cardiomyopathy Caused by Conditional Deletion of NEMO/IKK
in Cardiomyocytes
P. Kratsios ;
From the European Molecular Biology Laboratory (P.K., M.H., L.T., E.S., M.A.B., N.R., F.M.), Mouse Biology Unit, Campus "A. Buzzati-Traverso," Rome, Italy; Department of Evolutionary and Functional Biology (A.S., M.M.), University of Parma, Italy; and William Harvey Research Institute (K.S.), Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, United Kingdom.
* To whom correspondence should be addressed. E-mail: rosenthal{at}embl.it or fmourkio{at}stanford.edu.
Rationale: Insight into the function of nuclear factor (NF)-
B in the adult heart has been hampered by the embryonic lethality of constitutive NF-B inactivation.
Objective: The goal of the present study was therefore to gain insights into the role of NF-B pathway specifically in mouse cardiomyocytes by conditional deletion of the NF-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.
Key words: cardiomyopathy • nuclear factor
B •
heart failure •
knockout mice