Open AccessReview
Roles of A-Kinase Anchoring Proteins and Phosphodiesterases in the Cardiovascular System
J. Cardiovasc. Dev. Dis. 2018, 5(1), 14; doi:10.3390/jcdd5010014 -
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
Figures

Figure 1

Open AccessFeature PaperArticle
Hyperglycemia Alters the Structure and Hemodynamics of the Developing Embryonic Heart
J. Cardiovasc. Dev. Dis. 2018, 5(1), 13; doi:10.3390/jcdd5010013 -
Abstract
Congenital heart defects (CHDs) represent the most common form of human birth defects; approximately one-third of heart defects involve malformations of the outflow tract (OFT). Maternal diabetes increases the risk of CHD by 3–5 fold. During heart organogenesis, little is known about the
[...] Read more.
Congenital heart defects (CHDs) represent the most common form of human birth defects; approximately one-third of heart defects involve malformations of the outflow tract (OFT). Maternal diabetes increases the risk of CHD by 3–5 fold. During heart organogenesis, little is known about the effects of hyperglycemia on hemodynamics, which are critical to normal heart development. Heart development prior to septation in the chick embryo was studied under hyperglycemic conditions. Sustained hyperglycemic conditions were induced, raising the average plasma glucose concentration from 70 mg/dL to 180 mg/dL, akin to the fasting plasma glucose of a patient with diabetes. The OFTs were assessed for structural and hemodynamic alterations using optical coherence tomography (OCT), confocal microscopy, and microcomputed tomography. In hyperglycemic embryos, the endocardial cushions of the proximal OFT were asymmetric, and the OFTs curvature and torsion were significantly altered. The blood flow velocity through the OFT of hyperglycemic embryos was significantly decreased, including flow reversal in 30% of the cardiac cycle. Thus, hyperglycemia at the onset of gestation results in asymmetric proximal endocardial cushions, abnormal OFT curvature, and altered hemodynamics in the developing heart. If present in humans, these results may identify early developmental alterations that contribute to the increased risk for cardiac malformations in babies from diabetic mothers. Full article
Figures

Figure 1

Open AccessFeature PaperReview
A-Kinase Anchoring Protein-Lbc: A Molecular Scaffold Involved in Cardiac Protection
J. Cardiovasc. Dev. Dis. 2018, 5(1), 12; doi:10.3390/jcdd5010012 -
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
Figures

Figure 1

Open AccessFeature PaperReview
Functions of PDE3 Isoforms in Cardiac Muscle
J. Cardiovasc. Dev. Dis. 2018, 5(1), 10; doi:10.3390/jcdd5010010 -
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
Figures

Figure 1

Open AccessFeature PaperReview
Is an Appreciation of Isomerism the Key to Unlocking the Mysteries of the Cardiac Findings in Heterotaxy?
J. Cardiovasc. Dev. Dis. 2018, 5(1), 11; doi:10.3390/jcdd5010011 -
Abstract
Pediatric cardiologists treating patients with severe congenital cardiac defects define “visceral heterotaxy” on the basis of isomerism of the atrial appendages. The isomeric features represent an obvious manifestation of disruption of left-right asymmetry during embryonic development. Thus, there are two subsets of individuals
[...] Read more.
Pediatric cardiologists treating patients with severe congenital cardiac defects define “visceral heterotaxy” on the basis of isomerism of the atrial appendages. The isomeric features represent an obvious manifestation of disruption of left-right asymmetry during embryonic development. Thus, there are two subsets of individuals within the overall syndrome, with features of either right or left isomerism. Within the heart, it is only the atrial appendages that are truly isomeric. The remainder of the cardiac components shows variable morphology, as does the arrangement of the remaining body organs. Order is provided in this potentially chaotic arrangement simply by describing the specific features of each of the systems. These features as defined by clinicians, however, seem less well recognized by those investigating the developmental origins of the disruption of symmetry. Developmental biologists place much greater emphasis on ventricular looping. Although the direction of the loop can certainly be interpreted as representing an example of asymmetry, it is not comparable to the isomeric features that underscore the clinical syndromes. This is because, thus far, there is no evidence of ventricular isomerism, with the ventricles distinguished one from the other on the basis of their disparate anatomical features. In similar fashion, some consider transposition to represent abnormal lateralization, but again, clinical diagnosis depends on recognition of the lateralized features. In this review, therefore, we discuss the key questions that currently underscore the mismatch in the approaches to “lateralization” as taken by clinicians and developmental biologists. Full article
Figures

Figure 1

Open AccessReview
Epac Function and cAMP Scaffolds in the Heart and Lung
J. Cardiovasc. Dev. Dis. 2018, 5(1), 9; doi:10.3390/jcdd5010009 -
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
Figures

Figure 1

Open AccessFeature PaperReview
PDE4-Mediated cAMP Signalling
J. Cardiovasc. Dev. Dis. 2018, 5(1), 8; doi:10.3390/jcdd5010008 -
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
Figures

Figure 1

Open AccessFeature PaperReview
Polymorphisms/Mutations in A-Kinase Anchoring Proteins (AKAPs): Role in the Cardiovascular System
J. Cardiovasc. Dev. Dis. 2018, 5(1), 7; doi:10.3390/jcdd5010007 -
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
Figures

Figure 1

Open AccessFeature PaperReview
Cyclic Nucleotide-Directed Protein Kinases in Cardiovascular Inflammation and Growth
J. Cardiovasc. Dev. Dis. 2018, 5(1), 6; doi:10.3390/jcdd5010006 -
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
Figures

Figure 1

Open AccessFeature PaperEditorial
Acknowledgement to Reviewers of Journal of Cardiovascular Development and Disease in 2017
J. Cardiovasc. Dev. Dis. 2018, 5(1), 5; doi:10.3390/jcdd5010005 -
Abstract
Peer review is an essential part in the publication process, ensuring that Journal of Cardiovascular Development and Disease maintains high quality standards for its published papers[...] Full article
Open AccessFeature PaperReview
Imaging of PDE2- and PDE3-Mediated cGMP-to-cAMP Cross-Talk in Cardiomyocytes
J. Cardiovasc. Dev. Dis. 2018, 5(1), 4; doi:10.3390/jcdd5010004 -
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
Figures

Figure 1

Open AccessFeature PaperReview
Pre-Eclampsia and Eclampsia: An Update on the Pharmacological Treatment Applied in Portugal
J. Cardiovasc. Dev. Dis. 2018, 5(1), 3; doi:10.3390/jcdd5010003 -
Abstract
Pre-eclampsia and eclampsia are two hypertensive disorders of pregnancy, considered major causes of maternal and perinatal death worldwide. Pre-eclampsia is a multisystemic disease characterized by the development of hypertension after 20 weeks of gestation, with the presence of proteinuria or, in its absence,
[...] Read more.
Pre-eclampsia and eclampsia are two hypertensive disorders of pregnancy, considered major causes of maternal and perinatal death worldwide. Pre-eclampsia is a multisystemic disease characterized by the development of hypertension after 20 weeks of gestation, with the presence of proteinuria or, in its absence, of signs or symptoms indicative of target organ injury. Eclampsia represents the consequence of brain injuries caused by pre-eclampsia. The correct diagnosis and classification of the disease are essential, since the therapies for the mild and severe forms of pre-eclampsia are different. Thus, this review aims to describe the most advisable antepartum pharmacotherapy for pre-eclampsia and eclampsia applied in Portugal and based on several national and international available guidelines. Slow-release nifedipine is the most recommended drug for mild pre-eclampsia, and labetalol is the drug of choice for the severe form of the disease. Magnesium sulfate is used to prevent seizures caused by eclampsia. Corticosteroids are used for fetal lung maturation. Overall, the pharmacological prevention of these diseases is limited to low-dose aspirin, so it is important to establish the safest and most effective available treatment. Full article
Figures

Figure 1

Open AccessFeature PaperReview
Function of Adenylyl Cyclase in Heart: the AKAP Connection
J. Cardiovasc. Dev. Dis. 2018, 5(1), 2; doi:10.3390/jcdd5010002 -
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
Figures

Figure 1

Open AccessFeature PaperReview
Vertebrate Left-Right Asymmetry: What Can Nodal Cascade Gene Expression Patterns Tell Us?
J. Cardiovasc. Dev. Dis. 2018, 5(1), 1; doi:10.3390/jcdd5010001 -
Abstract
Laterality of inner organs is a wide-spread characteristic of vertebrates and beyond. It is ultimately controlled by the left-asymmetric activation of the Nodal signaling cascade in the lateral plate mesoderm of the neurula stage embryo, which results from a cilia-driven leftward flow of
[...] Read more.
Laterality of inner organs is a wide-spread characteristic of vertebrates and beyond. It is ultimately controlled by the left-asymmetric activation of the Nodal signaling cascade in the lateral plate mesoderm of the neurula stage embryo, which results from a cilia-driven leftward flow of extracellular fluids at the left-right organizer. This scenario is widely accepted for laterality determination in wildtype specimens. Deviations from this norm come in different flavors. At the level of organ morphogenesis, laterality may be inverted (situs inversus) or non-concordant with respect to the main body axis (situs ambiguus or heterotaxia). At the level of Nodal cascade gene activation, expression may be inverted, bilaterally induced, or absent. In a given genetic situation, patterns may be randomized or predominantly lacking laterality (absence or bilateral activation). We propose that the distributions of patterns observed may be indicative of the underlying molecular defects, with randomizations being primarily caused by defects in the flow-generating ciliary set-up, and symmetrical patterns being the result of impaired flow sensing, on the left, the right, or both sides. This prediction, the reasoning of which is detailed in this review, pinpoints functions of genes whose role in laterality determination have remained obscure. Full article
Figures

Figure 1

Open AccessFeature PaperArticle
Hemodynamics Modify Collagen Deposition in the Early Embryonic Chicken Heart Outflow Tract
J. Cardiovasc. Dev. Dis. 2017, 4(4), 24; doi:10.3390/jcdd4040024 -
Abstract
Blood flow is critical for normal cardiac development. Hemodynamic stimuli outside of normal ranges can lead to overt cardiac defects, but how early heart tissue remodels in response to altered hemodynamics is poorly understood. This study investigated changes in tissue collagen in response
[...] Read more.
Blood flow is critical for normal cardiac development. Hemodynamic stimuli outside of normal ranges can lead to overt cardiac defects, but how early heart tissue remodels in response to altered hemodynamics is poorly understood. This study investigated changes in tissue collagen in response to hemodynamic overload in the chicken embryonic heart outflow tract (OFT) during tubular heart stages (HH18 to HH24, ~24 h). A suture tied around the OFT at HH18 was tightened to constrict the lumen for ~24 h (constriction range at HH24: 15–60%). Expression of fibril collagens I and III and fibril organizing collagens VI and XIV were quantified at the gene and protein levels via qPCR and quantitative immunofluorescence. Collagen I was slightly elevated upstream of the band and in the cushions in banded versus control OFTs. Changes in collagen III were not observed. Collagen VI deposition was elevated downstream of the band, but not overall. Collagen XIV deposition increased throughout the OFT, and strongly correlated to lumen constriction. Interestingly, organization of collagen I fibrils was observed for the tighter banded embryos in regions that also showed increase in collagen XIV deposition, suggesting a potentially key role for collagens I and XIV in the structural adaptation of embryonic heart tissue to hemodynamic overload. Full article
Figures

Figure 1

Open AccessReview
The Role of Cerl2 in the Establishment of Left-Right Asymmetries during Axis Formation and Heart Development
J. Cardiovasc. Dev. Dis. 2017, 4(4), 23; doi:10.3390/jcdd4040023 -
Abstract
The formation of the asymmetric left-right (LR) body axis is one of the fundamental aspects of vertebrate embryonic development, and one still raising passionate discussions among scientists. Although the conserved role of nodal is unquestionable in this process, several of the details around
[...] Read more.
The formation of the asymmetric left-right (LR) body axis is one of the fundamental aspects of vertebrate embryonic development, and one still raising passionate discussions among scientists. Although the conserved role of nodal is unquestionable in this process, several of the details around this signaling cascade are still unanswered. To further understand this mechanism, we have been studying Cerberus-like 2 (Cerl2), an inhibitor of Nodal, and its role in the generation of asymmetries in the early vertebrate embryo. The absence of Cerl2 results in a wide spectrum of malformations commonly known as heterotaxia, which comprises defects in either global organ position (e.g., situs inversus totalis), reversed orientation of at least one organ (e.g., situs ambiguus), and mirror images of usually asymmetric paired organs (e.g., left or right isomerisms of the lungs). Moreover, these laterality defects are frequently associated with congenital heart diseases (e.g., transposition of the great arteries, or atrioventricular septal defects). Here, reviewing the knowledge on the establishment of LR asymmetry in mouse embryos, the emerging conclusion is that as necessary as is the activation of the Nodal signaling cascade, the tight control that Cerl2-mediates on Nodal signaling is equally important, and that generates a further regionalized LR genetic program in the proper time and space. Full article
Figures

Figure 1

Open AccessFeature PaperReview
The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation
J. Cardiovasc. Dev. Dis. 2017, 4(4), 22; doi:10.3390/jcdd4040022 -
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
Figures

Figure 1

Open AccessFeature PaperReview
The Physiopathology of Cardiorenal Syndrome: A Review of the Potential Contributions of Inflammation
J. Cardiovasc. Dev. Dis. 2017, 4(4), 21; doi:10.3390/jcdd4040021 -
Abstract
Inter-organ crosstalk plays an essential role in the physiological homeostasis of the heart and other organs, and requires a complex interaction between a host of cellular, molecular, and neural factors. Derangements in these interactions can initiate multi-organ dysfunction. This is the case, for
[...] Read more.
Inter-organ crosstalk plays an essential role in the physiological homeostasis of the heart and other organs, and requires a complex interaction between a host of cellular, molecular, and neural factors. Derangements in these interactions can initiate multi-organ dysfunction. This is the case, for instance, in the heart or kidneys where a pathological alteration in one organ can unfavorably affect function in another distant organ; attention is currently being paid to understanding the physiopathological consequences of kidney dysfunction on cardiac performance that lead to cardiorenal syndrome. Different cardiorenal connectors (renin–angiotensin or sympathetic nervous system activation, inflammation, uremia, etc.) and non-traditional risk factors potentially contribute to multi-organ failure. Of these, inflammation may be crucial as inflammatory cells contribute to over-production of eicosanoids and lipid second messengers that activate intracellular signaling pathways involved in pathogenesis. Indeed, inflammation biomarkers are often elevated in patients with cardiac or renal dysfunction. Epigenetics, a dynamic process that regulates gene expression and function, is also recognized as an important player in single-organ disease. Principal epigenetic modifications occur at the level of DNA (i.e., methylation) and histone proteins; aberrant DNA methylation is associated with pathogenesis of organ dysfunction through a number of mechanisms (inflammation, nitric oxide bioavailability, endothelin, etc.). Herein, we focus on the potential contribution of inflammation in pathogenesis of cardiorenal syndrome. Full article
Open AccessFeature PaperReview
Growth and Morphogenesis during Early Heart Development in Amniotes
J. Cardiovasc. Dev. Dis. 2017, 4(4), 20; doi:10.3390/jcdd4040020 -
Abstract
In this review, we will focus on the growth and morphogenesis of the developing heart, an aspect of cardiovascular development to which Antoon Moorman and colleagues have extensively contributed. Over the last decades, genetic studies and characterization of regionally regulated gene programs have
[...] Read more.
In this review, we will focus on the growth and morphogenesis of the developing heart, an aspect of cardiovascular development to which Antoon Moorman and colleagues have extensively contributed. Over the last decades, genetic studies and characterization of regionally regulated gene programs have provided abundant novel insights into heart development essential to understand the basis of congenital heart disease. Heart morphogenesis, however, is inherently a complex and dynamic three-dimensional process and we are far from understanding its cellular basis. Here, we discuss recent advances in studying heart morphogenesis and regionalization under the light of the pioneering work of Moorman and colleagues, which allowed the reinterpretation of regional gene expression patterns under a new morphogenetic framework. Two aspects of early heart formation will be discussed in particular: (1) the initial formation of the heart tube and (2) the formation of the cardiac chambers by the ballooning process. Finally, we emphasize that in addition to analyses based on fixed samples, new approaches including clonal analysis, single-cell sequencing, live-imaging and quantitative analysis of the data generated will likely lead to novel insights in understanding early heart tube regionalization and morphogenesis in the near future. Full article
Figures

Figure 1

Open AccessFeature PaperArticle
Kinking and Torsion Can Significantly Improve the Efficiency of Valveless Pumping in Periodically Compressed Tubular Conduits. Implications for Understanding of the Form-Function Relationship of Embryonic Heart Tubes
J. Cardiovasc. Dev. Dis. 2017, 4(4), 19; doi:10.3390/jcdd4040019 -
Abstract
Valveless pumping phenomena (peristalsis, Liebau-effect) can generate unidirectional fluid flow in periodically compressed tubular conduits. Early embryonic hearts are tubular conduits acting as valveless pumps. It is unclear whether such hearts work as peristaltic or Liebau-effect pumps. During the initial phase of its
[...] Read more.
Valveless pumping phenomena (peristalsis, Liebau-effect) can generate unidirectional fluid flow in periodically compressed tubular conduits. Early embryonic hearts are tubular conduits acting as valveless pumps. It is unclear whether such hearts work as peristaltic or Liebau-effect pumps. During the initial phase of its pumping activity, the originally straight embryonic heart is subjected to deforming forces that produce bending, twisting, kinking, and coiling. This deformation process is called cardiac looping. Its function is traditionally seen as generating a configuration needed for establishment of correct alignments of pulmonary and systemic flow pathways in the mature heart of lung-breathing vertebrates. This idea conflicts with the fact that cardiac looping occurs in all vertebrates, including gill-breathing fishes. We speculate that looping morphogenesis may improve the efficiency of valveless pumping. To test the physical plausibility of this hypothesis, we analyzed the pumping performance of a Liebau-effect pump in straight and looped (kinked) configurations. Compared to the straight configuration, the looped configuration significantly improved the pumping performance of our pump. This shows that looping can improve the efficiency of valveless pumping driven by the Liebau-effect. Further studies are needed to clarify whether this finding may have implications for understanding of the form-function relationship of embryonic hearts. Full article
Figures

Figure 1