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(Circulation. 2005;111:1645-1651.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

AFos Dissociates Cardiac Myocyte Hypertrophy and Expression of the Pathological Gene Program

Mark Y. Jeong, MD; Koichiro Kinugawa, MD, PhD; Charles Vinson, PhD; Carlin S. Long, MD

From the Cardiology Section, Denver Health Medical Center, Denver, Colo (M.Y.J., C.S.L.); Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan (K.K.); and National Cancer Institute, Bethesda, Md (C.V.). Dr Jeong is currently at the Department of Internal Medicine, Boston University Medical Center, Boston, Mass.

Correspondence to Carlin S. Long, MD, Cardiology Section, Denver Health Medical Center, 777 Bannock St, Mailstop 0960, Denver, CO 80204. E-mail clong{at}dhha.org

Received August 6, 2004; revision received November 17, 2004; accepted November 19, 2004.

Background— Although induction of activator protein-1 (AP-1) transcription factor activity has been observed in cardiac hypertrophy, a direct role for AP-1 in myocardial growth and gene expression remains obscure.

Methods and Results— Hypertrophy was induced in cultured neonatal rat cardiomyocytes with phenylephrine or overexpression of a constitutively active MAP3K, MKK6. In both treatment groups, induction of the pathological gene profile was observed, ie, expression of ß-myosin heavy chain (ßMHC), atrial/brain natriuretic peptides (ANP/BNP), and skeletal -actin (sACT) was increased, whereas expression for -myosin heavy chain (MHC) and the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) genes was repressed. The role of AP-1 in the hypertrophic phenotype was evaluated with the use of an adenoviral construct expressing a dominant negative mutant of the c-Fos proto-oncogene (AdAFos). Although AFos did not change the myocyte growth response, it abrogated the gene profile to both agonists, including the upregulation of both MHC and SERCA expression.

Conclusions— Although c-Fos/AP-1 is necessary for induction of the pathological/fetal gene program, it does not appear to be critical for cardiomyocyte hypertrophy.

Key Words: hypertrophy • signal transduction • myocytes • molecular biology

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