Electrical consequences of cardiac myocyte: fibroblast coupling

2015 ◽  
Vol 43 (3) ◽  
pp. 513-518 ◽  
Author(s):  
Lisa McArthur ◽  
Lisa Chilton ◽  
Godfrey L. Smith ◽  
Stuart A. Nicklin
Keyword(s):  
Heart Disease ◽  
Gap Junctions ◽  
Cardiac Myocyte ◽  
Cardiac Fibroblasts ◽  
Electrical Coupling ◽  
Ventricular Myocardium ◽  
Experimental Models ◽  
Cardiac Contraction ◽  
Cx43 Expression ◽  
Gap Junction Channel

Gap junctions are channels which allow electrical signals to propagate through the heart from the sinoatrial node and through the atria, conduction system and onwards to the ventricles, and hence are essential for co-ordinated cardiac contraction. Twelve connexin (Cx) proteins make up one gap junction channel, of which there are three main subtypes in the heart; Cx40, Cx43 and Cx45. In the cardiac myocyte, gap junctions are present mainly at the intercalated discs between neighbouring myocytes, and assist in rapid electrical conduction throughout the ventricular myocardium. Fibroblasts provide the structural skeleton of the myocardium and fibroblast numbers significantly increase in heart disease. Fibroblasts also express connexins and this may facilitate heterocellular electrical coupling between myocytes and fibroblasts in the setting of cardiac disease. Interestingly, cardiac fibroblasts have been demonstrated to increase Cx43 expression in experimental models of myocardial infarction and functional gap junctions between myocytes and fibroblasts have been reported. Therefore, in the setting of heart disease enhanced cardiac myocyte: fibroblast coupling may influence the electrical activity of the myocyte and contribute to arrhythmias.

Effects of diminished expression of connexin43 on gap junction number and size in ventricular myocardium

2000 ◽  
Vol 278 (5) ◽  
pp. H1662-H1670 ◽  
Author(s):  
Jeffrey E. Saffitz ◽  
Karen G. Green ◽  
William J. Kraft ◽  
Kenneth B. Schechtman ◽  
Kathryn A. Yamada
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Ventricular Myocytes ◽  
Intercellular Junctions ◽  
Ventricular Myocardium ◽  
Electron Microscopic ◽  
Confocal Immunofluorescence Microscopy ◽  
Normal Number ◽  
Gap Junction Channel ◽  
Junction Protein

Gap junction number and size vary widely in cardiac tissues with disparate conduction properties. Little is known about how tissue-specific patterns of intercellular junctions are established and regulated. To elucidate the relationship between gap junction channel protein expression and the structure of gap junctions, we analyzed Cx43 +/− mice, which have a genetic deficiency in expression of the major ventricular gap junction protein, connexin43 (Cx43). Quantitative confocal immunofluorescence microscopy revealed that diminished Cx43 signal in Cx43 +/− mice was due almost entirely to a reduction in the number of individual gap junctions (226 ± 52 vs. 150 ± 32 individual gap junctions/field in Cx43 +/+ and +/− ventricles, respectively; P < 0.05). The mean size of an individual gap junction was the same in both groups. Immunofluorescence results were confirmed with electron microscopic morphometry. Thus when connexin expression is diminished, ventricular myocytes become interconnected by a reduced number of large, normally sized gap junctions, rather than a normal number of smaller junctions. Maintenance of large gap junctions may be an adaptive response supporting safe ventricular conduction.

scholarly journals Altered conductance and permeability of Cx40 mutations associated with atrial fibrillation

2015 ◽  
Vol 146 (5) ◽  
pp. 387-398 ◽  
Author(s):  
Ana Santa Cruz ◽  
Gülistan Meşe ◽  
Laima Valiuniene ◽  
Peter R. Brink ◽  
Thomas W. White ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Gap Junctions ◽  
Lucifer Yellow ◽  
Electrical Coupling ◽  
Primary Component ◽  
Base Substitution ◽  
Cardiac Tissues ◽  
Gap Junction Channel ◽  
Channel Selectivity ◽  
Mutant Forms

Gap junctions ensure the rapid propagation of the action potential throughout the myocardium. Three mutant forms of connexin40 (Cx40; A96S, M163V, and G38D), the primary component of the atrial gap junction channel, are associated with atrial fibrillation and retain the ability to form functional channels. We determined the biophysical properties of these mutant gap junctions in transiently transfected HeLa and N2A cells. All three mutants showed macroscopic junctional conductances over the range of 0.5 to 40 nS, and voltage dependences comparable to those of wild-type (WT) Cx40. However, the unitary conductance of G38D channels was ∼1.6-fold higher than that of WT Cx40 channels (∼220 vs. ∼135 pS), whereas the unitary conductances of the A96S and M163V mutants were similar to that of WT Cx40. Furthermore, the M163V and G38D channels exhibited approximately two- and approximately fivefold higher permeability to the anionic dye Lucifer yellow (LY) relative to K+ (LY/K+) compared with that of WT Cx40, whereas A96S LY transfer was similar to that of WT (G38D &gt; M163V &gt; A96S ≈ Cx40WT). In contrast, G38D channels were almost impermeable to cationic ethidium bromide (EtBr), suggesting that G38D alters channel selectivity. Conversely, A96S and M163V channels showed enhanced EtBr permeability relative to WT Cx40, with the following permeability order: M163V &gt; A96S &gt; Cx40WT &gt; G38D. Altered conductive and permeability properties of mutant channels suggest an essential role for Cx40-mediated biochemical and electrical coupling in cardiac tissues. The altered properties of the three single-base substitution mutants may play a role in mechanisms of reentry arrhythmias.

Abstract 1400: Reduced Cx43 Expression Reduces Scar Formation After Coronary Ligation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yan Zhang ◽  
Evelyn M Kanter ◽  
Carla J Weinheimer ◽  
Erin M Gribben ◽  
Attila Kovacs ◽  
...  
Keyword(s):  
Wound Healing ◽  
Infarct Size ◽  
Smooth Muscle Actin ◽  
Electrical Coupling ◽  
Scar Formation ◽  
Cardiac Contraction ◽  
Collagen Deposition ◽  
Fibroblast Proliferation ◽  
Cx43 Expression ◽  
Junction Protein

Gap junctions mediate cell-to-cell electrical coupling required for synchronized cardiac contraction. They also serve as conduits for exchange of small signaling molecules. Reduction in connexin43 (Cx43), the major gap junction protein in ventricular tissue, likely underlies malignant arrhythmias in infarcted hearts. However, little is known about the role of reduced Cx43 expression in infarct healing. This study was performed to test the hypothesis that reduced expression of Cx43 influences cardiac fibroblast function and wound healing after myocardial infarction (MI). Methods: The left anterior coronary artery was ligated in wild-type (WTs) and Cx43-deficient (Cx43 +/− ) mice studied 6 d later. We quantified infarct size by Masson’s trichrome staining; cell proliferation by bromodeoxyuridine staining; matrix metallo-proteinase (MMP) activity in the noninfarcted, border and infarct regions (IZ) by zymography; myofibroblasts by α-smooth muscle actin (αSMA) immunostaining; and collagen deposition by Picrosirius red staining. Results: 6 d post-MI mean infarct size by trichrome staining was not different in Cx43 +/− (46±4%) vs WTs (46±5%). However, significant differences were observed in the Cx43 +/− infarcts. The area of unresorbed necrotic myocardium in the IZ was larger (p<0.01) in Cx43 +/− (40±11%, n=12) vs WTs (17±8%, n=6). Fibroblast proliferation in the IZ was increased (p<0.05) in Cx43 +/− (6.1±0.5%, n=4) vs WTs (4.1±0.7%, n=5), and activated MMP-2 was increased even more (p< 0.05) in the IZ of Cx43 +/− (40±6 relative density units, n=5) vs WTs (29±4 units, n=3) consistent with enhanced fibroblast proliferation. On the other hand, transformation to myofibroblasts in the IZ was diminished as reflected by reduced (p<0.01) αSMA-positive immunostaining in Cx43 +/− (32±16%, n=6) vs WTs (57±5%, n=12), and collagen deposition in the IZ was less (p<0.01) in Cx43 +/− (36±6%, n=6) vs WTs (50±13%, n=8) consistent with fewer myofibroblasts. Conclusion: Reduced Cx43 expression increases fibroblast proliferation and MMP activity, and reduces myofibro-blasts and collagen deposition indicating that remodeling of Cx43 can influence fibroblast function and delay scar formation and cardiac wound healing after MI.

Gap Junctions Involvement in Brain Hyperexcitability Phenomena

2008 ◽  
Vol 59 (11) ◽  
Author(s):  
Doru-Georg Margineanu
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Intercellular Communication ◽  
Experimental Models ◽  
Mammalian Brain ◽  
Cx43 Expression ◽  
Medical Need ◽  
Brain Hyperexcitability ◽  
Models Of Epilepsy ◽  
Anticonvulsant Effects

Hyperexcitability pathologies, epitomized by epilepsy, are a largely unmet medical need, asking for conceptual developments on the functioning of networks of inter-communicating neurons and glia. Intercellular communication via gap junction (GJ) channels is largely present in mammalian brain. The GJ channels are made of proteins, essentially the connexins (Cxs) widely expressed in brain and in peripheral organs, the most abundant being Cx43. Expression level of Cx43 appears elevated in epileptic brains. Many different compounds actually modify the strength of GJ intercellular communication, though none is specific for GJs. Reference GJ blockers have anticonvulsant effects in numerous experimental models of epilepsy and some data suggest that GJ blockade might specifically act on epileptic hyper-synchrony, a feature hardly targeted by current antiepileptic drugs. The involvement of GJs in migraine is also suggested by recent results.

scholarly journals Activated Cardiac Fibroblasts Control Contraction of Human Fibrotic Cardiac Microtissues by a β-Adrenoreceptor-Dependent Mechanism

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1270 ◽  
Author(s):  
Przemysław Błyszczuk ◽  
Christian Zuppinger ◽  
Ana Costa ◽  
Daria Nurzynska ◽  
Franca Di Meglio ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Experimental Models ◽  
Cardiac Contraction ◽  
Dependent Manner ◽  
Direct Stimulation ◽  
Beating Rate ◽  
Tgf Β1

Cardiac fibrosis represents a serious clinical problem. Development of novel treatment strategies is currently restricted by the lack of the relevant experimental models in a human genetic context. In this study, we fabricated self-aggregating, scaffold-free, 3D cardiac microtissues using human inducible pluripotent stem cell (iPSC)-derived cardiomyocytes and human cardiac fibroblasts. Fibrotic condition was obtained by treatment of cardiac microtissues with profibrotic cytokine transforming growth factor β1 (TGF-β1), preactivation of foetal cardiac fibroblasts with TGF-β1, or by the use of cardiac fibroblasts obtained from heart failure patients. In our model, TGF-β1 effectively induced profibrotic changes in cardiac fibroblasts and in cardiac microtissues. Fibrotic phenotype of cardiac microtissues was inhibited by treatment with TGF-β-receptor type 1 inhibitor SD208 in a dose-dependent manner. We observed that fibrotic cardiac microtissues substantially increased the spontaneous beating rate by shortening the relaxation phase and showed a lower contraction amplitude. Instead, no changes in action potential profile were detected. Furthermore, we demonstrated that contraction of human cardiac microtissues could be modulated by direct electrical stimulation or treatment with the β-adrenergic receptor agonist isoproterenol. However, in the absence of exogenous agonists, the β-adrenoreceptor blocker nadolol decreased beating rate of fibrotic cardiac microtissues by prolonging relaxation time. Thus, our data suggest that in fibrosis, activated cardiac fibroblasts could promote cardiac contraction rate by a direct stimulation of β-adrenoreceptor signalling. In conclusion, a model of fibrotic cardiac microtissues can be used as a high-throughput model for drug testing and to study cellular and molecular mechanisms of cardiac fibrosis.

Cloning and functional expression of a novel gap junction channel from the retina of Danio aquipinnatus

1998 ◽  
Vol 15 (6) ◽  
pp. 1137-1144 ◽  
Author(s):  
T.L.E. WAGNER ◽  
E.C. BEYER ◽  
D.G. McMAHON
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Blot Hybridization ◽  
Electrical Coupling ◽  
Neuroblastoma Cells ◽  
Functional Expression ◽  
Visual Signals ◽  
Reading Frame ◽  
Gap Junction Channel ◽  
Giant Danio

Electrical synapses, or gap junctions, are widely distributed in the vertebrate retina and are thought to play critical roles in the transmission and coding of visual signals. To investigate the molecular basis of this form of neural communication in the retina, we have isolated, characterized, and functionally expressed a cDNA for a gap junction channel derived from the retina of the teleost fish Danio aquipinnatus (giant danio). The cDNA contained an open reading frame of 1146 nucleotides encoding a connexin with a predicted molecular mass of 43.3 kDa which shared extensive identity with Rattus norvegicus Cx43 (78%). This protein (DACX43) contained several consensus phosphorylation sequences in the c-terminal region, some of which are conserved among Cx43 orthologs. RNA blot hybridization revealed that DACX43 was expressed in the brain as well as in the retina. In addition, Southern analysis suggested that there are multiple copies of DACX43, or other closely related sequences, in the Danio aquipinnatus genome. When DACX43 was expressed by stable transfection in gap-junction-deficient mouse N2A neuroblastoma cells, functional gap junctions were formed as indicated by dual whole-cell recordings of electrical coupling. We conclude that DACX43 is a connexin43 ortholog, which is expressed in the retina of Danio aquipinnatus, and when translated is able to form functional gap junction channels.

scholarly journals Selected clinical parameters and changes in cardiac morphology and function assessed by magnetic resonance imaging in patients with rheumatoid arthritis and ankylosing spondylitis without clinically apparent heart disease

2021 ◽  
Author(s):  
Wojciech Tański ◽  
Paweł Gać ◽  
Angelika Chachaj ◽  
Małgorzata Sobieszczańska ◽  
Rafał Poręba ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Disease ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Pericardial Fluid ◽  
Independent Effect ◽  
Left Ventricular Myocardium ◽  
Leukocyte Antigen ◽  
Independent Risk Factors ◽  
Occurrence Type

Abstract Background The aim of the study was to assess the relationship between the occurrence of rheumatoid arthritis (RA) and ankylosing spondylitis (AS) and the cardiac magnetic resonance (CMR) changes in people without clinically overt heart disease. Methods The study group consisted of 74 people (48.81 ± 11.35 years): 29 patients with RA, 23 patients with AS and 22 people from control group. Blood samples were taken to assess laboratory parameters, disease activity was determined using activity scales, and CMR was performed. Results It was shown that the factors independently related to higher left ventricular mass index are AS occurrence, human B27 leukocyte antigen occurrence, higher neutrophil gelatinase–associated lipocalin concentration (NGAL) and higher body mass index (BMI). The lower right ventricular ejection fraction is result of an independent effect of RA, AS and higher NGAL. RA presence, methotrexate use, higher rheumatoid factor titer, higher NGAL, older age and higher BMI should be considered independent risk factors for greater left ventricular myocardium water content. RA occurrence, AS occurrence, type 2 diabetes occurrence and a higher C-reactive protein concentration can be independently associated with a higher probability of non-ischemic left ventricular myocardium injury. Larger pericardial fluid volume is result of an independent effect of higher NGAL, higher anti-cyclic citrullinated peptide antibodies titer and higher DAS28 disease activity index. Use of steroids is protective factor against larger volume of pericardial fluid. Conclusions RA and AS in people without clinically apparent heart disease are associated with the occurrence of adverse changes in CMR. Key Points•RA and AS in people without clinically apparent heart disease are associated with the occurrence of adverse changes in CMR..•The independent risk factors for higher LVEF are AS occurrence, human B27 leukocyte antigen occurrence, higher NGAL concentration and higher BMI..•RA presence, methotrexate use, higher RF, higher NGAL, older age and higher BMI are independent risk factors for higher LV T2 ratio..•RA occurrence, AS occurrence, type 2 diabetes occurrence and a higher CRP are independently associated with a higher risk of non-ischemic LV myocardium injury..

scholarly journals Cardiac Exosomes in Ischemic Heart Disease—A Narrative Review

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 269
Author(s):  
Øystein Røsand ◽  
Morten Andre Høydal
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Cardiac Fibroblasts ◽  
Cell Communication ◽  
Bioactive Molecules ◽  
Ischemic Heart ◽  
Non Coding Rna ◽  
Stem And Progenitor Cells ◽  
Functional Involvement ◽  
Important Means

Ischemic heart disease (IHD) is the primary cause of death globally. IHD is associated with the disruption of blood supply to the heart muscles, which often results in myocardial infarction (MI) that further may progress to heart failure (HF). Exosomes are a subgroup of extracellular vesicles that can be secreted by virtually all types of cells, including cardiomyocytes, cardiac fibroblasts, endothelial cells, and stem and progenitor cells. Exosomes represent an important means of cell–cell communication through the transport of proteins, coding and non-coding RNA, and other bioactive molecules. Several studies show that exosomes play an important role in the progression of IHD, including endothelial dysfunction, the development of arterial atherosclerosis, ischemic reperfusion injury, and HF development. Recently, promising data have been shown that designates exosomes as carriers of cardioprotective molecules that enhance the survival of recipient cells undergoing ischemia. In this review, we summarize the functional involvement of exosomes regarding IHD. We also highlight the cardioprotective effects of native and bioengineered exosomes to IHD, as well as the possibility of using exosomes as natural biomarkers of cardiovascular diseases. Lastly, we discuss the opportunities and challenges that need to be addressed before exosomes can be used in clinical applications.

Freeze-fracture studies of frog atrial fibres

1976 ◽  
Vol 22 (2) ◽  
pp. 427-434
Author(s):  
F. Mazet ◽  
J. Cartaud
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Outer Membrane ◽  
Electrical Coupling ◽  
Freeze Fracture ◽  
Present Knowledge ◽  
Inner Membrane ◽  
Freeze Fracturing ◽  
Morphological Variant ◽  
Characteristic Features

The freeze-fracturing technique was used to characterize the junctional devices involved in the electrical coupling of frog atrial fibres. These fibres are connected by a type of junction which can be interpreted as a morphological variant of the “gap junction” or “nexus”. The most characteristic features are rows of 9-nm junctional particles forming single or anastomosed circular profiles on the inner membrane face, and corresponding pits on the outer membrane face. Very seldom aggregates consisting of few geometrically disposed 9-nm particles are found. The significance of the junctional structures in the atrial fibres is discussed, with respect to present knowledge about junctional features of gap junctions in various tissues, including embryonic ones.

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