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Cyclic Nucleotide Signaling and the Cardiovascular System
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Cyclic Nucleotide Signaling and the Cardiovascular System

A special issue of Journal of Cardiovascular Development and Disease (ISSN 2308-3425).

Deadline for manuscript submissions: closed (20 December 2017) | Viewed by 109663

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Thomas Brand

E-Mail Website
Guest Editor
National Heart & Lung Institute, Imperial College London, Hammersmith Campus, London W12 0NN, UK
Interests: heart development; cardiac pacemaker development and function; popeye genes; cAMP signaling
Special Issues, Collections and Topics in MDPI journals
Dr. Enno Klussmann

E-Mail Website
Guest Editor
1. Max‐Delbrück‐Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
2. DZHK (German Center for Cardiovascular Research), partner site Berlin, 10785 Berlin, Germany
Interests: A-kinase anchoring proteins (AKAPs); phosphodiesterases (PDEs); PKA; heart failure; compartmentalized cAMP signalling; vasopressin

Special Issue Information

Dear Colleagues,

The Journal of Cardiovascular Development and Disease (JCDD) is launching a Special Issue on “Cyclic Nucleotide Signaling and the Cardiovascular System”. JCDD is a peer reviewed online journal, in its fourth year of existence, which publishes review articles and original works on cardiovascular development and disease.

Cyclic nucleotides 3’,5’-adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) play important roles in the control of cardiovascular function under physiological and pathological conditions. They are produced by adenylate and guanylate cyclases, respectively, bound by different effector proteins, and are subsequently degraded by phosphodiesterases. These proteins form nanodomains in specific locations in cardiac myocytes, such as the plasma membrane, t-tubules, and the nuclear envelope. Thereby, a highly-compartmentalized regulation of essential functions of cardiac myocytes, such as calcium cycling, excitation-contraction coupling, and cell–cell cohesion, is achieved. The use of life cell imaging techniques, such as Förster resonance energy transfer (FRET)-based cyclic nucleotide biosensors and nanoscale scanning ion conductance microscopy (SICM), makes it possible to visualize cyclic nucleotide signaling at very high optical resolutions. Likewise, the importance of A-kinase anchoring proteins and phosphodiesterases to assemble specific signaling complexes in a compartment-specific manner have been thoroughly studied using a variety of advanced techniques. To this end, in cardiac myocytes several effector proteins are expressed namely protein kinase A (PKA) cGMP-dependent protein kinase (PKG), exchange factor directly activated by cAMP (EPAC), hyperpolarization-activated cyclic nucleotide gated channels (HCN) and the Popeye domain containing (POPDC) proteins, which participate in different aspects of signaling. Through the use of effector protein-specific agonists and antagonists and alternatively, with the help of genetic experiments, insight into their individual roles and cross-talk have been obtained. The importance of the cyclic nucleotide pathway in both health and disease cannot be underestimated and up-to-date reviews of this important scientific field will be provided.

Prof. Dr. Thomas Brand
Dr. Enno Klussmann
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Cardiovascular Development and Disease is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cyclic nucleotides

  • nanodomains

  • anchor proteins

  • phosphodiesterases

  • effector proteins

Published Papers (17 papers)

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Research

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6250 KiB  
Communication
Phosphodiesterases 3 and 4 Differentially Regulate the Funny Current, If, in Mouse Sinoatrial Node Myocytes
by Joshua R. St. Clair, Eric D. Larson, Emily J. Sharpe, Zhandi Liao and Catherine Proenza
J. Cardiovasc. Dev. Dis. 2017, 4(3), 10; https://doi.org/10.3390/jcdd4030010 - 01 Aug 2017
Cited by 10 | Viewed by 4698
Abstract
Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3′,5′-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac “funny current” (If) is among the cAMP-sensitive effectors that drive pacemaking in SAMs. If is produced [...] Read more.
Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3′,5′-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac “funny current” (If) is among the cAMP-sensitive effectors that drive pacemaking in SAMs. If is produced by hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels. Voltage-dependent gating of HCN channels is potentiated by cAMP, which acts either by binding directly to the channels or by activating the cAMP-dependent protein kinase (PKA), which phosphorylates them. PKA activity is required for signaling between β adrenergic receptors (βARs) and HCN channels in SAMs but the mechanism that constrains cAMP signaling to a PKA-dependent pathway is unknown. Phosphodiesterases (PDEs) hydrolyze cAMP and form cAMP signaling domains in other types of cardiomyocytes. Here we examine the role of PDEs in regulation of If in SAMs. If was recorded in whole-cell voltage-clamp experiments from acutely-isolated mouse SAMs in the absence or presence of PDE and PKA inhibitors, and before and after βAR stimulation. General PDE inhibition caused a PKA-independent depolarizing shift in the midpoint activation voltage (V1/2) of If at rest and removed the requirement for PKA in βAR-to-HCN signaling. PDE4 inhibition produced a similar PKA-independent depolarizing shift in the V1/2 of If at rest, but did not remove the requirement for PKA in βAR-to-HCN signaling. PDE3 inhibition produced PKA-dependent changes in If both at rest and in response to βAR stimulation. Our results suggest that PDE3 and PDE4 isoforms create distinct cAMP signaling domains that differentially constrain access of cAMP to HCN channels and establish the requirement for PKA in signaling between βARs and HCN channels in SAMs. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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Review

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16 pages, 659 KiB  
Review
Functional Significance of the Adcy10-Dependent Intracellular cAMP Compartments
by Sofya Pozdniakova and Yury Ladilov
J. Cardiovasc. Dev. Dis. 2018, 5(2), 29; https://doi.org/10.3390/jcdd5020029 - 11 May 2018
Cited by 17 | Viewed by 5498
Abstract
Mounting evidence confirms the compartmentalized structure of evolutionarily conserved 3′–5′-cyclic adenosine monophosphate (cAMP) signaling, which allows for simultaneous participation in a wide variety of physiological functions and ensures specificity, selectivity and signal strength. One important player in cAMP signaling is soluble adenylyl cyclase [...] Read more.
Mounting evidence confirms the compartmentalized structure of evolutionarily conserved 3′–5′-cyclic adenosine monophosphate (cAMP) signaling, which allows for simultaneous participation in a wide variety of physiological functions and ensures specificity, selectivity and signal strength. One important player in cAMP signaling is soluble adenylyl cyclase (sAC). The intracellular localization of sAC allows for the formation of unique intracellular cAMP microdomains that control various physiological and pathological processes. This review is focused on the functional role of sAC-produced cAMP. In particular, we examine the role of sAC-cAMP in different cellular compartments, such as cytosol, nucleus and mitochondria. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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17 pages, 11206 KiB  
Review
The Development of Compartmentation of cAMP Signaling in Cardiomyocytes: The Role of T-Tubules and Caveolae Microdomains
by Navneet K. Bhogal, Alveera Hasan and Julia Gorelik
J. Cardiovasc. Dev. Dis. 2018, 5(2), 25; https://doi.org/10.3390/jcdd5020025 - 03 May 2018
Cited by 20 | Viewed by 6181
Abstract
3′-5′-cyclic adenosine monophosphate (cAMP) is a signaling messenger produced in response to the stimulation of cellular receptors, and has a myriad of functional applications depending on the cell type. In the heart, cAMP is responsible for regulating the contraction rate and force; however, [...] Read more.
3′-5′-cyclic adenosine monophosphate (cAMP) is a signaling messenger produced in response to the stimulation of cellular receptors, and has a myriad of functional applications depending on the cell type. In the heart, cAMP is responsible for regulating the contraction rate and force; however, cAMP is also involved in multiple other functions. Compartmentation of cAMP production may explain the specificity of signaling following a stimulus. In particular, transverse tubules (T-tubules) and caveolae have been found to be critical structural components for the spatial confinement of cAMP in cardiomyocytes, as exemplified by beta-adrenergic receptor (β-ARs) signaling. Pathological alterations in cardiomyocyte microdomain architecture led to a disruption in compartmentation of the cAMP signal. In this review, we discuss the difference between atrial and ventricular cardiomyocytes in respect to microdomain organization, and the pathological changes of atrial and ventricular cAMP signaling in response to myocyte dedifferentiation. In addition, we review the role of localized phosphodiesterase (PDE) activity in constraining the cAMP signal. Finally, we discuss microdomain biogenesis and maturation of cAMP signaling with the help of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Understanding these mechanisms may help to overcome the detrimental effects of pathological structural remodeling. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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14 pages, 4599 KiB  
Review
Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction
by Si Chen, Walter E. Knight and Chen Yan
J. Cardiovasc. Dev. Dis. 2018, 5(2), 22; https://doi.org/10.3390/jcdd5020022 - 23 Apr 2018
Cited by 21 | Viewed by 6050
Abstract
Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of [...] Read more.
Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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18 pages, 970 KiB  
Review
cGMP Signaling and Vascular Smooth Muscle Cell Plasticity
by Moritz Lehners, Hyazinth Dobrowinski, Susanne Feil and Robert Feil
J. Cardiovasc. Dev. Dis. 2018, 5(2), 20; https://doi.org/10.3390/jcdd5020020 - 19 Apr 2018
Cited by 37 | Viewed by 8280
Abstract
Cyclic GMP regulates multiple cell types and functions of the cardiovascular system. This review summarizes the effects of cGMP on the growth and survival of vascular smooth muscle cells (VSMCs), which display remarkable phenotypic plasticity during the development of vascular diseases, such as [...] Read more.
Cyclic GMP regulates multiple cell types and functions of the cardiovascular system. This review summarizes the effects of cGMP on the growth and survival of vascular smooth muscle cells (VSMCs), which display remarkable phenotypic plasticity during the development of vascular diseases, such as atherosclerosis. Recent studies have shown that VSMCs contribute to the development of atherosclerotic plaques by clonal expansion and transdifferentiation to macrophage-like cells. VSMCs express a variety of cGMP generators and effectors, including NO-sensitive guanylyl cyclase (NO-GC) and cGMP-dependent protein kinase type I (cGKI), respectively. According to the traditional view, cGMP inhibits VSMC proliferation, but this concept has been challenged by recent findings supporting a stimulatory effect of the NO-cGMP-cGKI axis on VSMC growth. Here, we summarize the relevant studies with a focus on VSMC growth regulation by the NO-cGMP-cGKI pathway in cultured VSMCs and mouse models of atherosclerosis, restenosis, and angiogenesis. We discuss potential reasons for inconsistent results, such as the use of genetic versus pharmacological approaches and primary versus subcultured cells. We also explore how modern methods for cGMP imaging and cell tracking could help to improve our understanding of cGMP’s role in vascular plasticity. We present a revised model proposing that cGMP promotes phenotypic switching of contractile VSMCs to VSMC-derived plaque cells in atherosclerotic lesions. Regulation of vascular remodeling by cGMP is not only an interesting new therapeutic strategy, but could also result in side effects of clinically used cGMP-elevating drugs. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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15 pages, 2602 KiB  
Review
The Popeye Domain Containing Genes and Their Function as cAMP Effector Proteins in Striated Muscle
by Thomas Brand
J. Cardiovasc. Dev. Dis. 2018, 5(1), 18; https://doi.org/10.3390/jcdd5010018 - 13 Mar 2018
Cited by 21 | Viewed by 5702
Abstract
The Popeye domain containing (POPDC) genes encode transmembrane proteins, which are abundantly expressed in striated muscle cells. Hallmarks of the POPDC proteins are the presence of three transmembrane domains and the Popeye domain, which makes up a large part of the cytoplasmic portion [...] Read more.
The Popeye domain containing (POPDC) genes encode transmembrane proteins, which are abundantly expressed in striated muscle cells. Hallmarks of the POPDC proteins are the presence of three transmembrane domains and the Popeye domain, which makes up a large part of the cytoplasmic portion of the protein and functions as a cAMP-binding domain. Interestingly, despite the prediction of structural similarity between the Popeye domain and other cAMP binding domains, at the protein sequence level they strongly differ from each other suggesting an independent evolutionary origin of POPDC proteins. Loss-of-function experiments in zebrafish and mouse established an important role of POPDC proteins for cardiac conduction and heart rate adaptation after stress. Loss-of function mutations in patients have been associated with limb-girdle muscular dystrophy and AV-block. These data suggest an important role of these proteins in the maintenance of structure and function of striated muscle cells. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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21 pages, 1379 KiB  
Review
Using cAMP Sensors to Study Cardiac Nanodomains
by Katharina Schleicher and Manuela Zaccolo
J. Cardiovasc. Dev. Dis. 2018, 5(1), 17; https://doi.org/10.3390/jcdd5010017 - 13 Mar 2018
Cited by 22 | Viewed by 5057
Abstract
3′,5′-cyclic adenosine monophosphate (cAMP) signalling plays a major role in the cardiac myocyte response to extracellular stimulation by hormones and neurotransmitters. In recent years, evidence has accumulated demonstrating that the cAMP response to different extracellular agonists is not uniform: depending on the stimulus, [...] Read more.
3′,5′-cyclic adenosine monophosphate (cAMP) signalling plays a major role in the cardiac myocyte response to extracellular stimulation by hormones and neurotransmitters. In recent years, evidence has accumulated demonstrating that the cAMP response to different extracellular agonists is not uniform: depending on the stimulus, cAMP signals of different amplitudes and kinetics are generated in different subcellular compartments, eliciting defined physiological effects. In this review, we focus on how real-time imaging using fluorescence resonance energy transfer (FRET)-based reporters has provided mechanistic insight into the compartmentalisation of the cAMP signalling pathway and allowed for the precise definition of the regulation and function of subcellular cAMP nanodomains. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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24 pages, 1565 KiB  
Review
Roles of A-Kinase Anchoring Proteins and Phosphodiesterases in the Cardiovascular System
by Maria Ercu and Enno Klussmann
J. Cardiovasc. Dev. Dis. 2018, 5(1), 14; https://doi.org/10.3390/jcdd5010014 - 20 Feb 2018
Cited by 40 | Viewed by 7083
Abstract
A-kinase anchoring proteins (AKAPs) and cyclic nucleotide phosphodiesterases (PDEs) are essential enzymes in the cyclic adenosine 3’-5’ monophosphate (cAMP) signaling cascade. They establish local cAMP pools by controlling the intensity, duration and compartmentalization of cyclic nucleotide-dependent signaling. Various members of the AKAP and [...] Read more.
A-kinase anchoring proteins (AKAPs) and cyclic nucleotide phosphodiesterases (PDEs) are essential enzymes in the cyclic adenosine 3’-5’ monophosphate (cAMP) signaling cascade. They establish local cAMP pools by controlling the intensity, duration and compartmentalization of cyclic nucleotide-dependent signaling. Various members of the AKAP and PDE families are expressed in the cardiovascular system and direct important processes maintaining homeostatic functioning of the heart and vasculature, e.g., the endothelial barrier function and excitation-contraction coupling. Dysregulation of AKAP and PDE function is associated with pathophysiological conditions in the cardiovascular system including heart failure, hypertension and atherosclerosis. A number of diseases, including autosomal dominant hypertension with brachydactyly (HTNB) and type I long-QT syndrome (LQT1), result from mutations in genes encoding for distinct members of the two classes of enzymes. This review provides an overview over the AKAPs and PDEs relevant for cAMP compartmentalization in the heart and vasculature and discusses their pathophysiological role as well as highlights the potential benefits of targeting these proteins and their protein-protein interactions for the treatment of cardiovascular diseases. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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14 pages, 1182 KiB  
Review
A-Kinase Anchoring Protein-Lbc: A Molecular Scaffold Involved in Cardiac Protection
by Dario Diviani, Halima Osman and Erica Reggi
J. Cardiovasc. Dev. Dis. 2018, 5(1), 12; https://doi.org/10.3390/jcdd5010012 - 08 Feb 2018
Cited by 9 | Viewed by 5393
Abstract
Heart failure is a lethal disease that can develop after myocardial infarction, hypertension, or anticancer therapy. In the damaged heart, loss of function is mainly due to cardiomyocyte death and associated cardiac remodeling and fibrosis. In this context, A-kinase anchoring proteins (AKAPs) constitute [...] Read more.
Heart failure is a lethal disease that can develop after myocardial infarction, hypertension, or anticancer therapy. In the damaged heart, loss of function is mainly due to cardiomyocyte death and associated cardiac remodeling and fibrosis. In this context, A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that facilitate the spatiotemporal activation of the cyclic adenosine monophosphate (AMP)-dependent protein kinase (PKA) and other transduction enzymes involved in cardiac remodeling. AKAP-Lbc, a cardiac enriched anchoring protein, has been shown to act as a key coordinator of the activity of signaling pathways involved in cardiac protection and remodeling. This review will summarize and discuss recent advances highlighting the role of the AKAP-Lbc signalosome in orchestrating adaptive responses in the stressed heart. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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15 pages, 1558 KiB  
Review
Functions of PDE3 Isoforms in Cardiac Muscle
by Matthew Movsesian, Faiyaz Ahmad and Emilio Hirsch
J. Cardiovasc. Dev. Dis. 2018, 5(1), 10; https://doi.org/10.3390/jcdd5010010 - 06 Feb 2018
Cited by 34 | Viewed by 7214
Abstract
Isoforms in the PDE3 family of cyclic nucleotide phosphodiesterases have important roles in cyclic nucleotide-mediated signalling in cardiac myocytes. These enzymes are targeted by inhibitors used to increase contractility in patients with heart failure, with a combination of beneficial and adverse effects on [...] Read more.
Isoforms in the PDE3 family of cyclic nucleotide phosphodiesterases have important roles in cyclic nucleotide-mediated signalling in cardiac myocytes. These enzymes are targeted by inhibitors used to increase contractility in patients with heart failure, with a combination of beneficial and adverse effects on clinical outcomes. This review covers relevant aspects of the molecular biology of the isoforms that have been identified in cardiac myocytes; the roles of these enzymes in modulating cAMP-mediated signalling and the processes mediated thereby; and the potential for targeting these enzymes to improve the profile of clinical responses. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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16 pages, 1910 KiB  
Review
Epac Function and cAMP Scaffolds in the Heart and Lung
by Marion Laudette, Haoxiao Zuo, Frank Lezoualc’h and Martina Schmidt
J. Cardiovasc. Dev. Dis. 2018, 5(1), 9; https://doi.org/10.3390/jcdd5010009 - 03 Feb 2018
Cited by 24 | Viewed by 6965
Abstract
Evidence collected over the last ten years indicates that Epac and cAMP scaffold proteins play a critical role in integrating and transducing multiple signaling pathways at the basis of cardiac and lung physiopathology. Some of the deleterious effects of Epac, such as cardiomyocyte [...] Read more.
Evidence collected over the last ten years indicates that Epac and cAMP scaffold proteins play a critical role in integrating and transducing multiple signaling pathways at the basis of cardiac and lung physiopathology. Some of the deleterious effects of Epac, such as cardiomyocyte hypertrophy and arrhythmia, initially described in vitro, have been confirmed in genetically modified mice for Epac1 and Epac2. Similar recent findings have been collected in the lung. The following sections will describe how Epac and cAMP signalosomes in different subcellular compartments may contribute to cardiac and lung diseases. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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14 pages, 1241 KiB  
Review
PDE4-Mediated cAMP Signalling
by Bracy A. Fertig and George S. Baillie
J. Cardiovasc. Dev. Dis. 2018, 5(1), 8; https://doi.org/10.3390/jcdd5010008 - 31 Jan 2018
Cited by 56 | Viewed by 8672
Abstract
cAMP is the archetypal and ubiquitous second messenger utilised for the fine control of many cardiovascular cell signalling systems. The ability of cAMP to elicit cell surface receptor-specific responses relies on its compartmentalisation by cAMP hydrolysing enzymes known as phosphodiesterases. One family of [...] Read more.
cAMP is the archetypal and ubiquitous second messenger utilised for the fine control of many cardiovascular cell signalling systems. The ability of cAMP to elicit cell surface receptor-specific responses relies on its compartmentalisation by cAMP hydrolysing enzymes known as phosphodiesterases. One family of these enzymes, PDE4, is particularly important in the cardiovascular system, where it has been extensively studied and shown to orchestrate complex, localised signalling that underpins many crucial functions of the heart. In the cardiac myocyte, cAMP activates PKA, which phosphorylates a small subset of mostly sarcoplasmic substrate proteins that drive β-adrenergic enhancement of cardiac function. The phosphorylation of these substrates, many of which are involved in cardiac excitation-contraction coupling, has been shown to be tightly regulated by highly localised pools of individual PDE4 isoforms. The spatial and temporal regulation of cardiac signalling is made possible by the formation of macromolecular “signalosomes”, which often include a cAMP effector, such as PKA, its substrate, PDE4 and an anchoring protein such as an AKAP. Studies described in the present review highlight the importance of this relationship for individual cardiac PKA substrates and we provide an overview of how this signalling paradigm is coordinated to promote efficient adrenergic enhancement of cardiac function. The role of PDE4 also extends to the vascular endothelium, where it regulates vascular permeability and barrier function. In this distinct location, PDE4 interacts with adherens junctions to regulate their stability. These highly specific, non-redundant roles for PDE4 isoforms have far reaching therapeutic potential. PDE inhibitors in the clinic have been plagued with problems due to the active site-directed nature of the compounds which concomitantly attenuate PDE activity in all highly localised “signalosomes”. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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14 pages, 420 KiB  
Review
Polymorphisms/Mutations in A-Kinase Anchoring Proteins (AKAPs): Role in the Cardiovascular System
by Santosh V. Suryavanshi, Shweta M. Jadhav and Bradley K. McConnell
J. Cardiovasc. Dev. Dis. 2018, 5(1), 7; https://doi.org/10.3390/jcdd5010007 - 25 Jan 2018
Cited by 23 | Viewed by 5142
Abstract
A-kinase anchoring proteins (AKAPs) belong to a family of scaffolding proteins that bind to protein kinase A (PKA) by definition and a variety of crucial proteins, including kinases, phosphatases, and phosphodiesterases. By scaffolding these proteins together, AKAPs build a “signalosome” at specific subcellular [...] Read more.
A-kinase anchoring proteins (AKAPs) belong to a family of scaffolding proteins that bind to protein kinase A (PKA) by definition and a variety of crucial proteins, including kinases, phosphatases, and phosphodiesterases. By scaffolding these proteins together, AKAPs build a “signalosome” at specific subcellular locations and compartmentalize PKA signaling. Thus, AKAPs are important for signal transduction after upstream activation of receptors ensuring accuracy and precision of intracellular PKA-dependent signaling pathways. Since their discovery in the 1980s, AKAPs have been studied extensively in the heart and have been proven essential in mediating cyclic adenosine monophosphate (cAMP)-PKA signaling. Although expression of AKAPs in the heart is very low, cardiac-specific knock-outs of several AKAPs have a noteworthy cardiac phenotype. Moreover, single nucleotide polymorphisms and genetic mutations in crucial cardiac proteins play a substantial role in the pathophysiology of cardiovascular diseases (CVDs). Despite the significant role of AKAPs in the cardiovascular system, a limited amount of research has focused on the role of genetic polymorphisms and/or mutations in AKAPs in increasing the risk of CVDs. This review attempts to overview the available literature on the polymorphisms/mutations in AKAPs and their effects on human health with a special focus on CVDs. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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30 pages, 3193 KiB  
Review
Cyclic Nucleotide-Directed Protein Kinases in Cardiovascular Inflammation and Growth
by Nathan A. Holland, Jake T. Francisco, Sean C. Johnson, Joshua S. Morgan, Troy J. Dennis, Nishitha R. Gadireddy and David A. Tulis
J. Cardiovasc. Dev. Dis. 2018, 5(1), 6; https://doi.org/10.3390/jcdd5010006 - 23 Jan 2018
Cited by 7 | Viewed by 6748
Abstract
Cardiovascular disease (CVD), including myocardial infarction (MI) and peripheral or coronary artery disease (PAD, CAD), remains the number one killer of individuals in the United States and worldwide, accounting for nearly 18 million (>30%) global deaths annually. Despite considerable basic science and clinical [...] Read more.
Cardiovascular disease (CVD), including myocardial infarction (MI) and peripheral or coronary artery disease (PAD, CAD), remains the number one killer of individuals in the United States and worldwide, accounting for nearly 18 million (>30%) global deaths annually. Despite considerable basic science and clinical investigation aimed at identifying key etiologic components of and potential therapeutic targets for CVD, the number of individuals afflicted with these dreaded diseases continues to rise. Of the many biochemical, molecular, and cellular elements and processes characterized to date that have potential to control foundational facets of CVD, the multifaceted cyclic nucleotide pathways continue to be of primary basic science and clinical interest. Cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP) and their plethora of downstream protein kinase effectors serve ubiquitous roles not only in cardiovascular homeostasis but also in the pathogenesis of CVD. Already a major target for clinical pharmacotherapy for CVD as well as other pathologies, novel and potentially clinically appealing actions of cyclic nucleotides and their downstream targets are still being discovered. With this in mind, this review article focuses on our current state of knowledge of the cyclic nucleotide-driven serine (Ser)/threonine (Thr) protein kinases in CVD with particular emphasis on cyclic AMP-dependent protein kinase (PKA) and cyclic GMP-dependent protein kinase (PKG). Attention is given to the regulatory interactions of these kinases with inflammatory components including interleukin 6 signals, with G protein-coupled receptor and growth factor signals, and with growth and synthetic transcriptional platforms underlying CVD pathogenesis. This article concludes with a brief discussion of potential future directions and highlights the importance for continued basic science and clinical study of cyclic nucleotide-directed protein kinases as emerging and crucial controllers of cardiac and vascular disease pathologies. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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18 pages, 1656 KiB  
Review
Imaging of PDE2- and PDE3-Mediated cGMP-to-cAMP Cross-Talk in Cardiomyocytes
by Nikoleta Pavlaki and Viacheslav O. Nikolaev
J. Cardiovasc. Dev. Dis. 2018, 5(1), 4; https://doi.org/10.3390/jcdd5010004 - 19 Jan 2018
Cited by 21 | Viewed by 7172
Abstract
Cyclic nucleotides 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) are important second messengers that regulate cardiovascular function and disease by acting in discrete subcellular microdomains. Signaling compartmentation at these locations is often regulated by phosphodiesterases (PDEs). Some PDEs are also involved [...] Read more.
Cyclic nucleotides 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) are important second messengers that regulate cardiovascular function and disease by acting in discrete subcellular microdomains. Signaling compartmentation at these locations is often regulated by phosphodiesterases (PDEs). Some PDEs are also involved in the cross-talk between the two second messengers. The purpose of this review is to summarize and highlight recent findings about the role of PDE2 and PDE3 in cardiomyocyte cyclic nucleotide compartmentation and visualization of this process using live cell imaging techniques. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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15 pages, 2571 KiB  
Review
Function of Adenylyl Cyclase in Heart: the AKAP Connection
by Tanya A. Baldwin and Carmen W. Dessauer
J. Cardiovasc. Dev. Dis. 2018, 5(1), 2; https://doi.org/10.3390/jcdd5010002 - 16 Jan 2018
Cited by 34 | Viewed by 6399
Abstract
Cyclic adenosine monophosphate (cAMP), synthesized by adenylyl cyclase (AC), is a universal second messenger that regulates various aspects of cardiac physiology from contraction rate to the initiation of cardioprotective stress response pathways. Local pools of cAMP are maintained by macromolecular complexes formed by [...] Read more.
Cyclic adenosine monophosphate (cAMP), synthesized by adenylyl cyclase (AC), is a universal second messenger that regulates various aspects of cardiac physiology from contraction rate to the initiation of cardioprotective stress response pathways. Local pools of cAMP are maintained by macromolecular complexes formed by A-kinase anchoring proteins (AKAPs). AKAPs facilitate control by bringing together regulators of the cAMP pathway including G-protein-coupled receptors, ACs, and downstream effectors of cAMP to finely tune signaling. This review will summarize the distinct roles of AC isoforms in cardiac function and how interactions with AKAPs facilitate AC function, highlighting newly appreciated roles for lesser abundant AC isoforms. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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2217 KiB  
Review
The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation
by Graeme Barker, Euan Parnell, Boy Van Basten, Hanna Buist, David R. Adams and Stephen J. Yarwood
J. Cardiovasc. Dev. Dis. 2017, 4(4), 22; https://doi.org/10.3390/jcdd4040022 - 05 Dec 2017
Cited by 16 | Viewed by 6254
Abstract
The cyclic 3′,5′-adenosine monophosphate (cAMP) sensor enzyme, EPAC1, is a candidate drug target in vascular endothelial cells (VECs) due to its ability to attenuate proinflammatory cytokine signalling normally associated with cardiovascular diseases (CVDs), including atherosclerosis. This is through the EPAC1-dependent induction of the [...] Read more.
The cyclic 3′,5′-adenosine monophosphate (cAMP) sensor enzyme, EPAC1, is a candidate drug target in vascular endothelial cells (VECs) due to its ability to attenuate proinflammatory cytokine signalling normally associated with cardiovascular diseases (CVDs), including atherosclerosis. This is through the EPAC1-dependent induction of the suppressor of cytokine signalling gene, SOCS3, which targets inflammatory signalling proteins for ubiquitinylation and destruction by the proteosome. Given this important role for the EPAC1/SOCS3 signalling axis, we have used high throughput screening (HTS) to identify small molecule EPAC1 regulators and have recently isolated the first known non-cyclic nucleotide (NCN) EPAC1 agonist, I942. I942 therefore represents the first in class, isoform selective EPAC1 activator, with the potential to suppress pro-inflammatory cytokine signalling with a reduced risk of side effects associated with general cAMP-elevating agents that activate multiple response pathways. The development of augmented I942 analogues may therefore provide improved research tools to validate EPAC1 as a potential therapeutic target for the treatment of chronic inflammation associated with deadly CVDs. Full article
(This article belongs to the Special Issue Cyclic Nucleotide Signaling and the Cardiovascular System)
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