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(Circulation. 2003;108:664.)
© 2003 American Heart Association, Inc.

Brief Rapid Communications

A20 Is Dynamically Regulated in the Heart and Inhibits the Hypertrophic Response

Stuart A. Cook, MRCP, PhD; Mikhail S. Novikov, MD; Youngkeun Ahn, MD, PhD; Takashi Matsui, MD, PhD; Anthony Rosenzweig, MD

From the Program in Cardiovascular Gene Therapy, Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Anthony Rosenzweig, MD, Massachusetts General Hospital, 114 16th St, Rm 2600, Charlestown, MA 02129. E-mail arosenzweig{at}partners.org

Received September 10, 2002; de novo received May 2, 2003; revision received June 18, 2003; accepted June 19, 2003.

Background— Nuclear factor (NF)–B signaling has been implicated in cardiomyocyte hypertrophy. Here, we determine the cardiac regulation and biological activity of A20, an inhibitor of NF-B 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-B 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-B activation. Infection of cardiomyocytes with an adenoviral vector (Ad) encoding A20 inhibited tumor necrosis factor-–stimulated NF-B signaling with an efficacy comparable to dominant negative inhibitor of -B kinase ß (dnIKKß). Ad.dnIKKß-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-B signaling without sensitizing cardiomyocytes to apoptotic cell death.

Key Words: hypertrophy • apoptosis • inflammation

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