A20 is dynamically regulated in the heart and inhibits the hypertrophic response.
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.


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.
Cook
Stuart A
SA
Program in Cardiovascular Gene Therapy, Cardiovascular Research Centre and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass 02129, USA.
Novikov
Mikhail S
MS
Ahn
Youngkeun
Y
Matsui
Takashi
T
Rosenzweig
Anthony
A
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D006332:Cardiomegaly / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D019332:Endothelin-1 / Q000494:pharmacology; D025461:Feedback, Physiological; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009687:Nuclear Proteins; D010656:Phenylephrine / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013314:Stress, Mechanical; D014162:Transfection; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics
D000316:Adrenergic alpha-Agonists; D019332:Endothelin-1; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D010656:Phenylephrine; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse