Original Contribution

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. MillerAffiliated withDepartment of Pharmacology and Physiology, Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry
  • , Yujun CaiAffiliated withDepartment of Pharmacology and Physiology, Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry
  • , Masayoshi OikawaAffiliated withDepartment of Pharmacology and Physiology, Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry
  • , Tamlyn ThomasAffiliated withDepartment of Pharmacology and Physiology, Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry
  • , Wolfgang R. DostmannAffiliated withDepartment of Pharmacology, University of Vermont College of Medicine
  • , Manuela ZaccoloAffiliated withInstitute of Neuroscience and Psychology, University of Glasgow
  • , Keigi FujiwaraAffiliated withDepartment of Pharmacology and Physiology, Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry
  • , Chen YanAffiliated withDepartment of Pharmacology and Physiology, Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry Email author 

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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