Published Online
on March 28, 2005

A more recent version of this article appeared on April 5, 2005

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Submitted on August 6, 2004
Revised on November 17, 2004
Accepted on November 19, 2004

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

Mark Y. Jeong MD, Koichiro Kinugawa MD, PhD, Charles Vinson PhD, and 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.

^* To whom correspondence should be addressed. E-mail: clong{at}dhha.org.

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 -myosin heavy chain (MHC), 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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