Published online before print June 5, 2003, doi: 10.1161/01.RES.0000079794.57578.F1
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© 2003 American Heart Association, Inc.
Molecular Medicine |
Inducible cAMP Early Repressor (ICER) Is a Negative-Feedback Regulator of Cardiac Hypertrophy and an Important Mediator of Cardiac Myocyte Apoptosis in Response to ß-Adrenergic Receptor Stimulation
From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine and Department of Medicine (H.T., M.N., K.K., J.S.); Department of Gynecology, Obstetrics and Women’s Health (G.Y., C.A.M.), University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ.
Correspondence to Junichi Sadoshima, MD, PhD, Cardiovascular Research Institute, UMDNJ, New Jersey Medical School, 185 S Orange Ave, MSB G-609, Newark, NJ 07103. E-mail Sadoshju{at}umdnj.edu
Although stimulation of the ß-adrenergic receptor increases levels of cAMP and activation of the cAMP response element (CRE) in cardiac myocytes, the role of the signaling mechanism regulated by cAMP in hypertrophy and apoptosis is not well understood. In this study we show that protein expression of inducible cAMP early repressor (ICER), an endogenous inhibitor of CRE-mediated transcription, is induced by stimulation of isoproterenol (ISO), a ß-adrenergic agonist with a peak at 
12 hours and persisting for more than 24 hours in neonatal rat cardiac myocytes. ICER is also upregulated by phenylephrine but not by endothelin-1. Continuous infusion of ISO also increased ICER in the rat heart in vivo. Overexpression of ICER significantly attenuated ISO- and phenylephrine-induced cardiac hypertrophy but did not inhibit endothelin-1–induced cardiac hypertrophy. Overexpression of ICER also stimulated cardiac myocyte apoptosis. Antisense inhibition of ICER significantly enhanced ß-adrenergic hypertrophy, whereas it significantly inhibited ß-adrenergic cardiac myocyte apoptosis, suggesting that endogenous ICER works as an important regulator of cardiac hypertrophy and apoptosis. Inhibition of CRE-mediated transcription by dominant-negative CRE binding protein inhibited cardiac hypertrophy, whereas it stimulated cardiac myocyte apoptosis, thereby mimicking the effect of ICER. Both ISO and ICER reduced expression of Bcl-2, an antiapoptotic molecule, whereas antisense ICER prevented ISO-induced downregulation of Bcl-2. These results suggest that ICER is upregulated by cardiac hypertrophic stimuli increasing CRE-mediated transcription in cardiac myocytes and acts as a negative regulator of hypertrophy and a positive mediator of apoptosis, in part through both inhibition of CRE-mediated transcription and downregulation of Bcl-2.
Key Words: cardiac hypertrophy • apoptosis • gene regulation • cell signaling/signal transduction
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