Abstract
Background:
Nuclear factor (NF)-kappaB signaling has been implicated in cardiomyocyte hypertrophy. Here, we determine the cardiac regulation and biological activity of A20, an inhibitor of NF-kappaB signaling.
Methods and results:
Mice were subjected to aortic banding, and A20 expression was examined. A20 mRNA upregulation (4.3+/-1.5-fold; P<0.05) was detected 3 hours after banding, coinciding with peak NF-kappaB activation. A20 was also upregulated in cultured neonatal cardiomyocytes stimulated with phenylephrine or endothelin-1 (2.8+/-0.6- and 4+/-1.1-fold, respectively; P<0.05), again paralleling NF-kappaB activation. Infection of cardiomyocytes with an adenoviral vector (Ad) encoding A20 inhibited tumor necrosis factor-alpha-stimulated NF-kappaB signaling with an efficacy comparable to dominant negative inhibitor of kappa-B kinase beta (dnIKKbeta). Ad.dnIKKbeta-infected cardiomyocytes exhibited increased apoptosis when they were serum starved or subjected to hypoxia-reoxygenation, whereas Ad.A20-infected cardiomyocytes did not. Expression of Ad.A20 inhibited the hypertrophic response in cardiomyocytes stimulated with phenylephrine or endothelin-1.
Conclusions:
A20 is dynamically regulated during acute biomechanical stress in the heart and functions to attenuate cardiac hypertrophy through the inhibition of NF-kappaB signaling without sensitizing cardiomyocytes to apoptotic cell death.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adrenergic alpha-Agonists / pharmacology
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Animals
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Animals, Newborn
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Apoptosis / drug effects
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Cardiomegaly / metabolism
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Cardiomegaly / prevention & control*
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Cells, Cultured
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Cysteine Endopeptidases
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Endothelin-1 / pharmacology
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Feedback, Physiological
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I-kappa B Proteins / biosynthesis
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I-kappa B Proteins / genetics
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Intracellular Signaling Peptides and Proteins
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Mice
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Myocardium / metabolism*
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Nuclear Proteins
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Phenylephrine / pharmacology
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Proteins / genetics
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Proteins / pharmacology
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Proteins / physiology*
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Stress, Mechanical
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Transfection
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Tumor Necrosis Factor alpha-Induced Protein 3
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Tumor Necrosis Factor-alpha / pharmacology
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Up-Regulation / genetics
Substances
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Adrenergic alpha-Agonists
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Endothelin-1
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I-kappa B Proteins
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Nfkbia protein, mouse
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Nuclear Proteins
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Proteins
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RNA, Messenger
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Phenylephrine
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Tumor Necrosis Factor alpha-Induced Protein 3
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Cysteine Endopeptidases
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Tnfaip3 protein, mouse