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

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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.

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Acknowledgments

We thank Dr. Soyeon Lim, Dr. Nhat-Tu Le, and Dr. Yuichiro Takei (University of Rochester, USA) for providing cardiac fibroblasts. We thank Dr. Kees Jalink (The Netherlands Cancer Institute, The Netherlands) for providing the permission to use the Epac1-H30-cyto construct. We thank Dr. Rajesh Kukreja (Virginia Commonwealth University, USA) for providing Ad-PKG I shRNA. We thank Dr. Jian-Dong Li (University of Rochester, USA) for providing the Smad-binding element-luciferase reporter construct and plasmids encoding Smad2 and Smad3. This work was supported by an American Heart Association Established Investigator Award 0740021N (to C.Y.), NIH grants HL088400 and HL077789 (to C.Y.), American Heart Association Predoctoral Fellowship 0815730D (to C.L.M.), This work was also supported by NIH HL68891 (to W.R.D.) and the Totman Trust for Biomedical Research (to W.R.D.) and by the British Heart Foundation PG/07/091/23698 (to M.Z.).

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  1. Department of Pharmacology and Physiology, Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box CVRI, Rochester, NY, 14642, USA

    Clint L. Miller, Yujun Cai, Masayoshi Oikawa, Tamlyn Thomas, Keigi Fujiwara & Chen Yan

  2. Department of Pharmacology, University of Vermont College of Medicine, Burlington, VT, 05405, USA

    Wolfgang R. Dostmann

  3. Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK

    Manuela Zaccolo

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  1. Clint L. Miller
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Miller, C.L., Cai, Y., Oikawa, M. et al. Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart. Basic Res Cardiol 106, 1023–1039 (2011). https://doi.org/10.1007/s00395-011-0228-2

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