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.
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.
Authors: Danyan Xu; Ning Li; Yuxia He; Valeriy Timofeyev; Ling Lu; Hsing-Ju Tsai; In-Hae Kim; Dipika Tuteja; Robertino Karlo P Mateo; Anil Singapuri; Benjamin B Davis; Reginald Low; Bruce D Hammock; Nipavan Chiamvimonvat Journal: Proc Natl Acad Sci U S A Date: 2006-11-27 Impact factor: 11.205
Authors: Brooke C Harrison; Charles R Roberts; David B Hood; Meghan Sweeney; Jody M Gould; Erik W Bush; Timothy A McKinsey Journal: Mol Cell Biol Date: 2004-12 Impact factor: 4.272