Basic Research in Cardiology

, Volume 106, Issue 6, pp 1023–1039

Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart

  • Clint L. Miller
  • Yujun Cai
  • Masayoshi Oikawa
  • Tamlyn Thomas
  • Wolfgang R. Dostmann
  • Manuela Zaccolo
  • Keigi Fujiwara
  • Chen Yan
Original Contribution

Abstract

Cardiac fibroblasts become activated and differentiate to smooth muscle-like myofibroblasts in response to hypertension and myocardial infarction (MI), resulting in extracellular matrix (ECM) remodeling, scar formation and impaired cardiac function. cAMP and cGMP-dependent signaling have been implicated in cardiac fibroblast activation and ECM synthesis. Dysregulation of cyclic nucleotide phosphodiesterase (PDE) activity/expression is also associated with various diseases and several PDE inhibitors are currently available or in development for treating these pathological conditions. The objective of this study is to define and characterize the specific PDE isoform that is altered during cardiac fibroblast activation and functionally important for regulating myofibroblast activation and ECM synthesis. We have found that Ca2+/calmodulin-stimulated PDE1A isoform is specifically induced in activated cardiac myofibroblasts stimulated by Ang II and TGF-β in vitro as well as in vivo within fibrotic regions of mouse, rat, and human diseased hearts. Inhibition of PDE1A function via PDE1-selective inhibitor or PDE1A shRNA significantly reduced Ang II or TGF-β-induced myofibroblast activation, ECM synthesis, and pro-fibrotic gene expression in rat cardiac fibroblasts. Moreover, the PDE1 inhibitor attenuated isoproterenol-induced interstitial fibrosis in mice. Mechanistic studies revealed that PDE1A modulates unique pools of cAMP and cGMP, predominantly in perinuclear and nuclear regions of cardiac fibroblasts. Further, both cAMP-Epac-Rap1 and cGMP-PKG signaling was involved in PDE1A-mediated regulation of collagen synthesis. These results suggest that induction of PDE1A plays a critical role in cardiac fibroblast activation and cardiac fibrosis, and targeting PDE1A may lead to regression of the adverse cardiac remodeling associated with various cardiac diseases.

Keywords

Cyclic nucleotide Phosphodiesterase Myofibroblast Cardiac fibrosis 

Supplementary material

395_2011_228_MOESM1_ESM.pdf (4.8 mb)
Online Supplement 1 (PDF 4939 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Clint L. Miller
    • 1
  • Yujun Cai
    • 1
  • Masayoshi Oikawa
    • 1
  • Tamlyn Thomas
    • 1
  • Wolfgang R. Dostmann
    • 2
  • Manuela Zaccolo
    • 3
  • Keigi Fujiwara
    • 1
  • Chen Yan
    • 1
  1. 1.Department of Pharmacology and Physiology, Department of Medicine, Aab Cardiovascular Research InstituteUniversity of Rochester School of Medicine and DentistryRochesterUSA
  2. 2.Department of PharmacologyUniversity of Vermont College of MedicineBurlingtonUSA
  3. 3.Institute of Neuroscience and PsychologyUniversity of GlasgowGlasgowUK

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