Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart

Chen Yan, Clint L. Miller, Jun Ichi Abe

Research output: Contribution to journalReview article

67 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)489-501
Number of pages13
JournalCirculation research
Volume100
Issue number4
DOIs
StatePublished - Mar 1 2007

Fingerprint

Cyclic Nucleotides
Phosphoric Diester Hydrolases
Cardiac Myocytes
Down-Regulation
Heart Failure
Phosphodiesterase 3 Inhibitors
Apoptosis
Cyclic GMP
Cardiovascular System
Muscle Cells
Gene Expression
Mortality
Enzymes
Proteins
Therapeutics

Keywords

  • Apoptosis
  • Heart failure
  • ICER
  • PDE
  • cAMP

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart. / Yan, Chen; Miller, Clint L.; Abe, Jun Ichi.

In: Circulation research, Vol. 100, No. 4, 01.03.2007, p. 489-501.

Research output: Contribution to journalReview article

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