Heart failure is a multifactorial disease, characterized by ventricular hypertrophy, dilation, myocyte death, fibrosis, and contractile dysfunction. cAMP and cGMP contribute to both normal physiological adaptation and pathological remodeling, which is controlled by multiple spatially discrete and functionally distinct cyclic nucleotide signaling. Cyclic nucleotide phosphodiesterases (PDEs) that catalyze the degradation reaction are essential for maintaining homeostasis, compartmentalization and specificity of cyclic nucleotides. Increasing evidence has indicated that alterations in the expression/activation of different PDEs represent causative mechanisms for a number of diseases, many of which have been found to be improved by pharmacologically targeting these PDEs. Thus, defining the specific PDE isoforms responsible for the pathological cardiac remodeling and dysfunction could be essential for developing new therapeutic strategies. Through systematic screening for PDEs that are altered in diseased hearts, we found that Ca2+/calmodulin-stimulated PDE1 family members (including PDE1A and 1C) are significantly up-regulated in failing hearts. However, the roles and underlying mechanisms of PDE1 family members in cardiac disease progression are still not well understood. Our in vitro studies showed that PDE1A plays important roles in cardiac myocyte hypertrophy and fibroblast activation, which is likely mediated by cGMP/PKG-dependent inhibition of myocardin-related transcription factor (MRTF) known to be critical for cardiac myocyte hypertrophy and fibroblast activation. To explore the role of PDE1A in animal disease models in vivo, we have recently developed a floxed PDE1A mouse strain, allowing in vivo depletion of PDE1A either globally or in a cell-type specific manner. In contrast, PDE1C plays a critical role in promoting myocyte death, likely by antagonizing the protective adenosine/cAMP signaling. PDE1C also promotes myocyte hypertrophy, but via a different molecular mechanism that involves cAMP/PKA- dependent phosphorylation of histone deacetylase HDAC5 and nucleocytoplasmic shuttling. PDE1C appears to interact with TRPC1/3 (transient receptor potential channels) that may functions as a source of Ca2+ for stimulating PDE1C activation. In our preliminary in vivo study, global PDE1C knockout mice showed a tendency towards protection from pressure overload-induced cardiac remodeling and dysfunction. Based on these exciting preliminary findings, we hypothesize that both PDE1A and PDE1C play essential but distinct roles in pathological cardiac remodeling and failure through modulating different cyclic nucleotide signaling pathways in cardiac myocytes and/or fibroblasts. The overall objective of this proposal is to investigate the functional roles and underlying mechanisms of distinct PDE1A- and PDE1C-regulated cyclic nucleotide signaling in the key pathogenic processes of cardiac remodeling and heart failure, by using well-established in vitro and in vivo models. Findings from these studies may facilitate the development of novel therapeutic strategies and help predict the cardiac side effects when using PDE1 inhibitors in treating other diseases.

Public Health Relevance

to Public health Heart failure remains a leading cause of mortality in the United States. The underlying molecular mechanisms of cardiac remodeling and dysfunction in heart failure are not fully understood. Our goal is to obtain a better understanding of the molecular and cellular bases of heart failure, which may lead to the identification of novel therapeutic targets and strategies for treating heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088400-07
Application #
9249660
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2007-04-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
7
Fiscal Year
2017
Total Cost
$383,750
Indirect Cost
$133,750
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Zhang, Yishuai; Knight, Walter; Chen, Si et al. (2018) Multiprotein Complex With TRPC (Transient Receptor Potential-Canonical) Channel, PDE1C (Phosphodiesterase 1C), and A2R (Adenosine A2 Receptor) Plays a Critical Role in Regulating Cardiomyocyte cAMP and Survival. Circulation 138:1988-2002
Chen, Si; Knight, Walter E; Yan, Chen (2018) Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction. J Cardiovasc Dev Dis 5:
Zhang, Yi-Shuai; Li, Jian-Dong; Yan, Chen (2018) An update on vinpocetine: New discoveries and clinical implications. Eur J Pharmacol 819:30-34
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Wu, Mei-Ping; Zhang, Yi-Shuai; Xu, Xiangbin et al. (2017) Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis. Cardiovasc Drugs Ther 31:157-166
Knight, Walter E; Chen, Si; Zhang, Yishuai et al. (2016) PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction. Proc Natl Acad Sci U S A 113:E7116-E7125
Wu, Mei-ping; Zhang, Yi-shuai; Zhou, Qian-mei et al. (2016) Higenamine protects ischemia/reperfusion induced cardiac injury and myocyte apoptosis through activation of ?2-AR/PI3K/AKT signaling pathway. Pharmacol Res 104:115-23
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Lee, Ji-Yun; Komatsu, Kensei; Lee, Byung-Cheol et al. (2015) Vinpocetine inhibits Streptococcus pneumoniae-induced upregulation of mucin MUC5AC expression via induction of MKP-1 phosphatase in the pathogenesis of otitis media. J Immunol 194:5990-8
Susuki-Miyata, Seiko; Miyata, Masanori; Lee, Byung-Cheol et al. (2015) Cross-talk between PKA-C? and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi. Proc Natl Acad Sci U S A 112:E1800-9

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