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(Circulation Research. 2007;100:489.)
© 2007 American Heart Association, Inc.

Reviews

Regulation of Phosphodiesterase 3 and Inducible cAMP Early Repressor in the Heart

Chen Yan, Clint L. Miller, Jun-ichi Abe

From the Center for Cardiovascular Research, Aab Institute of Biomedical Science, University of Rochester School of Medicine and Dentistry, NY.

Correspondence to Chen Yan, PhD, University of Rochester, 601 Elmwood Ave, Box 679, Rochester, NY 14642. E-mail Chen_Yan{at}urmc.rochester.edu

This Review is part of a thematic series on Phosphodiesterases, which includes the following articles:

Compartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of Cyclic Nucleotide Phosphodiesterases
Regulation of Phosphodiesterase 3 and Inducible cAMP Early Repressor in the Heart
Overview of Phosphodiesterases and Their Regulation
cAMP and cGMP Signaling Crosstalk: Role of Phosphodiesterases and Implications for Cardiac Pathophysiology
cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System: A Molecular Toolbox for Generating Compartmentalized cAMP Signaling

   Phosphodiesterase 5

David A. Kass Editor

Growing evidence suggests that multiple spatially, temporally, and functionally distinct pools of cyclic nucleotides exist and regulate cardiac performance, from acute myocardial contractility to chronic gene expression and cardiac structural remodeling. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP and cyclic GMP, regulate the amplitude, duration, and compartmentation of cyclic nucleotide-mediated signaling. In particular, PDE3 enzymes play a major role in regulating cAMP metabolism in the cardiovascular system. PDE3 inhibitors, by raising cAMP content, have acute inotropic and vasodilatory effects in treating congestive heart failure but have increased mortality in long-term therapy. PDE3A expression is downregulated in human and animal failing hearts. In vitro, inhibition of PDE3A function is associated with myocyte apoptosis through sustained induction of a transcriptional repressor ICER (inducible cAMP early repressor) and thereby inhibition of antiapoptotic molecule Bcl-2 expression. Sustained induction of ICER may also cause the change of other protein expression implicated in human and animal failing hearts. These data suggest that the downregulation of PDE3A observed in failing hearts may play a causative role in the progression of heart failure, in part, by inducing ICER and promoting cardiac myocyte dysfunction. Hence, strategies that maintain PDE3A function may represent an attractive approach to circumvent myocyte apoptosis and cardiac dysfunction.

Key Words: cAMP • PDE • ICER • heart failure • apoptosis

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