Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: Implication in heart failure

Bo Ding, Jun Ichi Abe, Heng Wei, Qunhua Huang, Richard A. Walsh, Carlos A. Molina, Allan Zhao, Junichi Sadoshima, Burns C. Blaxall, Bradford C. Berk, Chen Yan

Research output: Contribution to journalArticle

136 Scopus citations

Abstract

Background - Myocyte apoptosis plays an important role in pathological cardiac remodeling and the progression of heart failure. cAMP signaling is crucial in the regulation of myocyte apoptosis and cardiac remodeling. Multiple cAMP-hydrolyzing phosphodiesterases (PDEs), such as PDE3 and PDE4, coexist in cardiomyocytes and elicit differential temporal/spatial regulation of cAMP signaling. However, the role of PDE3 and PDE4 in the regulation of cardiomyocyte apoptosis remains unclear. Although chronic treatment with PDE3 inhibitors increases mortality in patients with heart failure, the contribution of PDE3 expression/activity in heart failure is not well known. Methods and Results - In this study we report that PDE3A expression and activity were significantly reduced in human failing hearts as well as mouse hearts with chronic pressure overload. In primary cultured cardiomyocytes, chronic inhibition of PDE3 but not PDE4 activity by pharmacological agents or adenovirus-delivered antisense PDE3A promoted cardiomyocyte apoptosis. Both angiotensin II (Ang II) and the β-adrenergic receptor agonist isoproterenol selectively induced a sustained downregulation of PDE3A expression and induced cardiomyocyte apoptosis. Restoring PDE3A via adenovirus-delivered expression of wild-type PDE3A1 completely blocked Ang H- and isoproterenol-induced cardiomyocyte apoptosis, suggesting the critical role of PDE3A reduction in cardiomyocyte apoptosis. Moreover, we defined a crucial role for inducible cAMP early repressor expression in PDE3A reduction-mediated cardiomyocyte apoptosis. Conclusions - Our results suggest that PDE3A reduction and consequent inducible cAMP early repressor induction are critical events in Ang II- and isoproterenol-induced cardiomyocyte apoptosis and may contribute to the development of heart failure. Drugs that maintain PDE3A function may represent an attractive therapeutic approach to treat heart failure.

Original languageEnglish
Pages (from-to)2469-2476
Number of pages8
JournalCirculation
Volume111
Issue number19
DOIs
StatePublished - 17 May 2005

    Fingerprint

Keywords

  • Apoptosis
  • Heart failure
  • Phosphodiesterases

Cite this

Ding, B., Abe, J. I., Wei, H., Huang, Q., Walsh, R. A., Molina, C. A., Zhao, A., Sadoshima, J., Blaxall, B. C., Berk, B. C., & Yan, C. (2005). Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: Implication in heart failure. Circulation, 111(19), 2469-2476. https://doi.org/10.1161/01.CIR.0000165128.39715.87