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Isolation and Physiological Analysis of Mouse Cardiomyocytes
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Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: implication in heart failure

Bo Ding1, Jun-Ichi Abe1, Heng Wei1

  • 1Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Science, Rochester, NY (B.D., J.A., H.W., Q.H., B.C. Berk, C.Y.); Case Western Reserve University, Cleveland, Ohio (R.A.W.); University of Medicine and Dentistry of New Jersey, Newark (C.A.M., J.S.); University of Pittsburgh, Pittsburgh, Pa (A.Z.); and Center for Cellular and Molecular Cardiology, University of Rochester, Rochester, NY (B.C. Blaxall).

Circulation
|May 4, 2005
PubMed
Abstract

Insights

Reduced phosphodiesterase 3A (PDE3A) expression promotes heart failure by increasing cardiomyocyte apoptosis. Maintaining PDE3A function may offer a new therapeutic strategy for heart failure patients.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Myocyte apoptosis is a key factor in pathological cardiac remodeling and heart failure progression.
  • Cyclic adenosine monophosphate (cAMP) signaling regulates myocyte apoptosis and cardiac remodeling.
  • The roles of phosphodiesterases (PDEs), specifically PDE3 and PDE4, in cardiomyocyte apoptosis are not fully understood.

Purpose of the Study:

  • To investigate the role of PDE3 and PDE4 in regulating cardiomyocyte apoptosis.
  • To determine the contribution of PDE3 expression and activity in heart failure.
  • To explore the therapeutic potential of targeting PDE3A in heart failure.

Main Methods:

  • Quantitative analysis of PDE3A expression and activity in human and mouse failing hearts.
  • In vitro studies using primary cultured cardiomyocytes treated with pharmacological inhibitors and gene delivery methods (adenovirus).
  • Assessment of apoptosis induction by angiotensin II (Ang II) and isoproterenol, and the effect of PDE3A restoration.

Main Results:

  • PDE3A expression and activity were significantly reduced in failing hearts.
  • Inhibition of PDE3, but not PDE4, promoted cardiomyocyte apoptosis.
  • Angiotensin II and isoproterenol downregulated PDE3A expression, inducing apoptosis, which was blocked by restoring PDE3A.
  • Inducible cAMP early repressor expression was identified as crucial in PDE3A reduction-mediated apoptosis.

Conclusions:

  • Reduced PDE3A expression and induced cAMP early repressor are critical in Ang II- and isoproterenol-induced cardiomyocyte apoptosis.
  • These events may contribute to the development of heart failure.
  • Maintaining PDE3A function presents a potential therapeutic strategy for heart failure.

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