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Choquet C, Sicard P, Vahdat J, Nguyen THM, Kober F, Varlet I, Bernard M, Richard S, Kelly RG, Lalevée N, Miquerol L. Nkx2-5 Loss of Function in the His-Purkinje System Hampers Its Maturation and Leads to Mechanical Dysfunction. J Cardiovasc Dev Dis 2023; 10:jcdd10050194. [PMID: 37233161 DOI: 10.3390/jcdd10050194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/24/2023] [Accepted: 04/25/2023] [Indexed: 05/27/2023] Open
Abstract
The ventricular conduction or His-Purkinje system (VCS) mediates the rapid propagation and precise delivery of electrical activity essential for the synchronization of heartbeats. Mutations in the transcription factor Nkx2-5 have been implicated in a high prevalence of developing ventricular conduction defects or arrhythmias with age. Nkx2-5 heterozygous mutant mice reproduce human phenotypes associated with a hypoplastic His-Purkinje system resulting from defective patterning of the Purkinje fiber network during development. Here, we investigated the role of Nkx2-5 in the mature VCS and the consequences of its loss on cardiac function. Neonatal deletion of Nkx2-5 in the VCS using a Cx40-CreERT2 mouse line provoked apical hypoplasia and maturation defects of the Purkinje fiber network. Genetic tracing analysis demonstrated that neonatal Cx40-positive cells fail to maintain a conductive phenotype after Nkx2-5 deletion. Moreover, we observed a progressive loss of expression of fast-conduction markers in persistent Purkinje fibers. Consequently, Nkx2-5-deleted mice developed conduction defects with progressively reduced QRS amplitude and RSR' complex associated with higher duration. Cardiac function recorded by MRI revealed a reduction in the ejection fraction in the absence of morphological changes. With age, these mice develop a ventricular diastolic dysfunction associated with dyssynchrony and wall-motion abnormalities without indication of fibrosis. These results highlight the requirement of postnatal expression of Nkx2-5 in the maturation and maintenance of a functional Purkinje fiber network to preserve contraction synchrony and cardiac function.
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Affiliation(s)
- Caroline Choquet
- CNRS, IBDM, UMR7288, Aix-Marseille Université, 13009 Marseille, France
- INSERM, MMG, Aix-Marseille Université, 13385 Marseille, France
| | - Pierre Sicard
- INSERM, CNRS, PHYMEDEXP, University de Montpellier, 34295 Montpellier, France
| | - Juliette Vahdat
- CNRS, IBDM, UMR7288, Aix-Marseille Université, 13009 Marseille, France
| | - Thi Hong Minh Nguyen
- CNRS, IBDM, UMR7288, Aix-Marseille Université, 13009 Marseille, France
- INSERM, TAGC, UMR1090, Aix-Marseille Université, 13288 Marseille, France
- Department of Life Sciences, University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, Hanoi 10072, Vietnam
| | - Frank Kober
- CNRS, CRMBM, Aix-Marseille Université, 13385 Marseille, France
| | - Isabelle Varlet
- CNRS, CRMBM, Aix-Marseille Université, 13385 Marseille, France
| | - Monique Bernard
- CNRS, CRMBM, Aix-Marseille Université, 13385 Marseille, France
| | - Sylvain Richard
- INSERM, CNRS, PHYMEDEXP, University de Montpellier, 34295 Montpellier, France
| | - Robert G Kelly
- CNRS, IBDM, UMR7288, Aix-Marseille Université, 13009 Marseille, France
| | - Nathalie Lalevée
- INSERM, TAGC, UMR1090, Aix-Marseille Université, 13288 Marseille, France
- INSERM, C2VN, UMR1263, Aix-Marseille Université, 13005 Marseille, France
| | - Lucile Miquerol
- CNRS, IBDM, UMR7288, Aix-Marseille Université, 13009 Marseille, France
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Yin YQ, Zhong Y, Zhu Y, Tian L. Changes in gap junction proteins Connexin30.2 and Connexin40 expression in the sinoatrial node of rats with dexmedetomidine-induced sinus bradycardia. BRAZILIAN JOURNAL OF ANESTHESIOLOGY (ELSEVIER) 2022; 72:768-773. [PMID: 35618083 PMCID: PMC9659980 DOI: 10.1016/j.bjane.2022.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 05/12/2022] [Accepted: 05/14/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Dexmedetomidine (Dex) is widely used, and its most common side effect is bradycardia. The complete mechanism through which Dex induces bradycardia has not been elucidated. This research investigates the expression of gap junction proteins Connexin30.2 (Cx30.2) and Connexin40 (Cx40) within the sinoatrial node of rats with Dex-induced sinus bradycardia. METHODS Eighty rats were randomly assigned to five groups. Saline was administered to rats in Group C. In the other four groups, the rats were administered Dex to induce bradycardia. In groups D1 and D2, the rats were administered Dex at a loading dose of 30 μg.kg-1 and 100 μg.kg-1 for 10 min, then at 15 μg.kg-1.h-1 and 50 μg.kg-1.h-1 for 120 min separately. The rats in group D1A and D2A were administered Dex in the same way as in group D1 and D2; however, immediately after the administration of the loading dose, 0.5 mg atropine was administered intravenously, and then at 0.5 mg.kg-1.h-1 for 120 min. The sinoatrial node was acquired after intravenous infusion was completed. Quantitative real-time polymerase chain reaction and western blot analyses were performed to measure mRNA and protein expression of Cx30.2 and Cx40, respectively. RESULTS The expression of Cx30.2 increased, whereas the expression of Cx40 decreased within the sinoatrial node of rats with Dex-induced sinus bradycardia. Atropine reversed the effects of Dex on the expression of gap junction proteins. CONCLUSION Dex possibly altered the expression of gap junction proteins to slow down cardiac conduction velocity in the sinoatrial node.
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Affiliation(s)
| | - Yi Zhong
- Affiliated Hospital of Guizhou Medical University, Department of Anesthesiology, Guiyang, China.
| | - Yu Zhu
- Guizhou Medical University, Guiyang, China
| | - Lei Tian
- Guizhou Medical University, Guiyang, China
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Remodeling of Cardiac Gap Junctional Cell-Cell Coupling. Cells 2021; 10:cells10092422. [PMID: 34572071 PMCID: PMC8465208 DOI: 10.3390/cells10092422] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/03/2021] [Accepted: 09/08/2021] [Indexed: 12/29/2022] Open
Abstract
The heart works as a functional syncytium, which is realized via cell-cell coupling maintained by gap junction channels. These channels connect two adjacent cells, so that action potentials can be transferred. Each cell contributes a hexameric hemichannel (=connexon), formed by protein subuntis named connexins. These hemichannels dock to each other and form the gap junction channel. This channel works as a low ohmic resistor also allowing the passage of small molecules up to 1000 Dalton. Connexins are a protein family comprising of 21 isoforms in humans. In the heart, the main isoforms are Cx43 (the 43 kDa connexin; ubiquitous), Cx40 (mostly in atrium and specific conduction system), and Cx45 (in early developmental states, in the conduction system, and between fibroblasts and cardiomyocytes). These gap junction channels are mainly located at the polar region of the cardiomyocytes and thus contribute to the anisotropic pattern of cardiac electrical conductivity. While in the beginning the cell–cell coupling was considered to be static, similar to an anatomically defined structure, we have learned in the past decades that gap junctions are also subject to cardiac remodeling processes in cardiac disease such as atrial fibrillation, myocardial infarction, or cardiomyopathy. The underlying remodeling processes include the modulation of connexin expression by e.g., angiotensin, endothelin, or catecholamines, as well as the modulation of the localization of the gap junctions e.g., by the direction and strength of local mechanical forces. A reduction in connexin expression can result in a reduced conduction velocity. The alteration of gap junction localization has been shown to result in altered pathways of conduction and altered anisotropy. In particular, it can produce or contribute to non-uniformity of anisotropy, and thereby can pre-form an arrhythmogenic substrate. Interestingly, these remodeling processes seem to be susceptible to certain pharmacological treatment.
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Zhang J, Vincent KP, Peter AK, Klos M, Cheng H, Huang SM, Towne JK, Ferng D, Gu Y, Dalton ND, Chan Y, Li R, Peterson KL, Chen J, McCulloch AD, Knowlton KU, Ross RS. Cardiomyocyte Expression of ZO-1 Is Essential for Normal Atrioventricular Conduction but Does Not Alter Ventricular Function. Circ Res 2020; 127:284-297. [PMID: 32345129 DOI: 10.1161/circresaha.119.315539] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
RATIONALE ZO-1 (Zonula occludens-1), a plasma membrane-associated scaffolding protein regulates signal transduction, transcription, and cellular communication. Global deletion of ZO-1 in the mouse is lethal by embryonic day 11.5. The function of ZO-1 in cardiac myocytes (CM) is largely unknown. OBJECTIVE To determine the function of CM ZO-1 in the intact heart, given its binding to other CM proteins that have been shown instrumental in normal cardiac conduction and function. METHODS AND RESULTS We generated ZO-1 CM-specific knockout (KO) mice using α-Myosin Heavy Chain-nuclear Cre (ZO-1cKO) and investigated physiological and electrophysiological function by echocardiography, surface ECG and conscious telemetry, intracardiac electrograms and pacing, and optical mapping studies. ZO-1cKO mice were viable, had normal Mendelian ratios, and had a normal lifespan. Ventricular morphometry and function were not significantly different between the ZO-1cKO versus control (CTL) mice, basally in young or aged mice, or even when hearts were subjected to hemodynamic loading. Atrial mass was increased in ZO-1cKO. Electrophysiological and optical mapping studies indicated high-grade atrioventricular (A-V) block in ZO-1cKO comparing to CTL hearts. While ZO-1-associated proteins such as vinculin, connexin 43, N-cadherin, and α-catenin showed no significant change with the loss of ZO-1, Connexin-45 and Coxsackie-adenovirus (CAR) proteins were reduced in atria of ZO-1cKO. Further, with loss of ZO-1, ZO-2 protein was increased significantly in ventricular CM in a presumed compensatory manner but was still not detected in the AV nodal myocytes. Importantly, the expression of the sodium channel protein NaV1.5 was altered in AV nodal cells of the ZO-1cKO versus CTL. CONCLUSIONS ZO-1 protein has a unique physiological role in cardiac nodal tissue. This is in alignment with its known interaction with CAR and Cx45, and a new function in regulating the expression of NaV1.5 in AV node. Uniquely, ZO-1 is dispensable for function of the working myocardium.
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Affiliation(s)
- Jianlin Zhang
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Kevin P Vincent
- Department of Bioengineering (K.P.V., A.D.M.), University of California San Diego, La Jolla, CA
| | - Angela K Peter
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Matthew Klos
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Hongqiang Cheng
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Selina M Huang
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Jordan K Towne
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Debbie Ferng
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Yusu Gu
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Nancy D Dalton
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Yunghang Chan
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Ruixia Li
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Kirk L Peterson
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Ju Chen
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
| | - Andrew D McCulloch
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
- Department of Bioengineering (K.P.V., A.D.M.), University of California San Diego, La Jolla, CA
| | | | - Robert S Ross
- From the Department of Medicine (J.Z., A.K.P., M.K., H.C., S.M.H., J.K.T., D.F., Y.G., N.D.D., Y.C., J.K.T., D.F., Y.G., N.D.D., Y.C., R.L., K.L.P., J.C., A.D.M., R.S.R.), University of California San Diego, La Jolla, CA
- Veterans Administration Healthcare, Cardiology Section, San Diego, CA (R.S.R.)
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Coronel-Cruz C, Sánchez I, Hernández-Tellez B, Rodríguez-Mata V, Pinzón-Estrada E, Castell-Rodríguez A, Pérez-Armendariz E. Connexin 30.2 is expressed in exocrine vascular endothelial and ductal epithelial cells throughout pancreatic postnatal development. Acta Histochem 2018; 120:558-565. [PMID: 30100173 DOI: 10.1016/j.acthis.2018.06.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 06/10/2018] [Accepted: 06/29/2018] [Indexed: 02/08/2023]
Abstract
Previously we have demonstrated that the GJ protein connexin 30.2 (Cx30.2) is expressed in pancreatic beta cells and endothelial cells (ECs) of the islet. In the present study, we address whether Cx30.2 is expressed in the exocrine pancreas, including its vascular system. For this, adult mouse pancreatic sections were double labeled with specific antibodies against Cx30.2 and CD31, an endothelial cell marker, or with anti-α-actin smooth muscle, a smooth muscle cell (SMC) marker or anti-mucin-1, a marker of epithelial ductal cells, using immunofluorescence (IF) studies. Cx30.2-IF hot spots were found at junctional membranes of exocrine ECs and SMCs of blood vessels. Furthermore, Cx30.2 was localized in mucin-1 positive cells or epithelial ductal cells. Using immunohistochemistry (IHC) studies, it was found that in vessels and ducts of different diameters, Cx30.2 was also expressed in these cell types. In addition, it was found that Cx30.2 is already expressed in these cell types in pancreatic sections of 3, 14 and 21 days postpartum. Moreover, this cell specific pattern of expression was also found in the adult rat, hamster and guinea pig pancreas. Expression of Cx30.2 mRNA and protein in the pancreas of all these species was confirmed by RT-PCR and Western blot studies. Overall, our results suggest that intercellular coupling mediated by Cx30.2 intercellular channels may synchronize the functional activity of ECs and SMCs of vascular cells, as well as of epithelial ductal cells after birth.
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Abstract
Cardiac arrhythmias can follow disruption of the normal cellular electrophysiological processes underlying excitable activity and their tissue propagation as coherent wavefronts from the primary sinoatrial node pacemaker, through the atria, conducting structures and ventricular myocardium. These physiological events are driven by interacting, voltage-dependent, processes of activation, inactivation, and recovery in the ion channels present in cardiomyocyte membranes. Generation and conduction of these events are further modulated by intracellular Ca2+ homeostasis, and metabolic and structural change. This review describes experimental studies on murine models for known clinical arrhythmic conditions in which these mechanisms were modified by genetic, physiological, or pharmacological manipulation. These exemplars yielded molecular, physiological, and structural phenotypes often directly translatable to their corresponding clinical conditions, which could be investigated at the molecular, cellular, tissue, organ, and whole animal levels. Arrhythmogenesis could be explored during normal pacing activity, regular stimulation, following imposed extra-stimuli, or during progressively incremented steady pacing frequencies. Arrhythmic substrate was identified with temporal and spatial functional heterogeneities predisposing to reentrant excitation phenomena. These could arise from abnormalities in cardiac pacing function, tissue electrical connectivity, and cellular excitation and recovery. Triggering events during or following recovery from action potential excitation could thereby lead to sustained arrhythmia. These surface membrane processes were modified by alterations in cellular Ca2+ homeostasis and energetics, as well as cellular and tissue structural change. Study of murine systems thus offers major insights into both our understanding of normal cardiac activity and its propagation, and their relationship to mechanisms generating clinical arrhythmias.
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Affiliation(s)
- Christopher L-H Huang
- Physiological Laboratory and the Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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Tse G, Lai ETH, Yeo JM, Tse V, Wong SH. Mechanisms of Electrical Activation and Conduction in the Gastrointestinal System: Lessons from Cardiac Electrophysiology. Front Physiol 2016; 7:182. [PMID: 27303305 PMCID: PMC4885840 DOI: 10.3389/fphys.2016.00182] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 05/06/2016] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal (GI) tract is an electrically excitable organ system containing multiple cell types, which coordinate electrical activity propagating through this tract. Disruption in its normal electrophysiology is observed in a number of GI motility disorders. However, this is not well characterized and the field of GI electrophysiology is much less developed compared to the cardiac field. The aim of this article is to use the established knowledge of cardiac electrophysiology to shed light on the mechanisms of electrical activation and propagation along the GI tract, and how abnormalities in these processes lead to motility disorders and suggest better treatment options based on this improved understanding. In the first part of the article, the ionic contributions to the generation of GI slow wave and the cardiac action potential (AP) are reviewed. Propagation of these electrical signals can be described by the core conductor theory in both systems. However, specifically for the GI tract, the following unique properties are observed: changes in slow wave frequency along its length, periods of quiescence, synchronization in short distances and desynchronization over long distances. These are best described by a coupled oscillator theory. Other differences include the diminished role of gap junctions in mediating this conduction in the GI tract compared to the heart. The electrophysiology of conditions such as gastroesophageal reflux disease and gastroparesis, and functional problems such as irritable bowel syndrome are discussed in detail, with reference to ion channel abnormalities and potential therapeutic targets. A deeper understanding of the molecular basis and physiological mechanisms underlying GI motility disorders will enable the development of better diagnostic and therapeutic tools and the advancement of this field.
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Affiliation(s)
- Gary Tse
- Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, University of Hong KongHong Kong, China
| | - Eric Tsz Him Lai
- Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, University of Hong KongHong Kong, China
| | - Jie Ming Yeo
- School of Medicine, Imperial College LondonLondon, UK
| | - Vivian Tse
- Department of Physiology, McGill UniversityMontreal, QC, Canada
| | - Sunny Hei Wong
- Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Sciences, Chinese University of Hong KongHong Kong, China
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Balakrishnan M, Chakravarthy VS, Guhathakurta S. Simulation of Cardiac Arrhythmias Using a 2D Heterogeneous Whole Heart Model. Front Physiol 2015; 6:374. [PMID: 26733873 PMCID: PMC4685512 DOI: 10.3389/fphys.2015.00374] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 11/23/2015] [Indexed: 01/11/2023] Open
Abstract
Simulation studies of cardiac arrhythmias at the whole heart level with electrocardiogram (ECG) gives an understanding of how the underlying cell and tissue level changes manifest as rhythm disturbances in the ECG. We present a 2D whole heart model (WHM2D) which can accommodate variations at the cellular level and can generate the ECG waveform. It is shown that, by varying cellular-level parameters like the gap junction conductance (GJC), excitability, action potential duration (APD) and frequency of oscillations of the auto-rhythmic cell in WHM2D a large variety of cardiac arrhythmias can be generated including sinus tachycardia, sinus bradycardia, sinus arrhythmia, sinus pause, junctional rhythm, Wolf Parkinson White syndrome and all types of AV conduction blocks. WHM2D includes key components of the electrical conduction system of the heart like the SA (Sino atrial) node cells, fast conducting intranodal pathways, slow conducting atriovenctricular (AV) node, bundle of His cells, Purkinje network, atrial, and ventricular myocardial cells. SA nodal cells, AV nodal cells, bundle of His cells, and Purkinje cells are represented by the Fitzhugh-Nagumo (FN) model which is a reduced model of the Hodgkin-Huxley neuron model. The atrial and ventricular myocardial cells are modeled by the Aliev-Panfilov (AP) two-variable model proposed for cardiac excitation. WHM2D can prove to be a valuable clinical tool for understanding cardiac arrhythmias.
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Affiliation(s)
- Minimol Balakrishnan
- Department of Biotechnology, Indian Institute of Technology MadrasChennai, India
| | | | - Soma Guhathakurta
- Department of Engineering Design, Indian Institute of Technology MadrasChennai, India
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Absence of connexin43 and connexin45 does not disturb pre- and peri-implantation development. ZYGOTE 2015; 24:457-64. [DOI: 10.1017/s0967199415000386] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
SummaryGap junctional intercellular communication is assumed to play an important role during pre- and peri-implantation development. In this study, we eliminated connexin43 (Cx43) and connexin45 (Cx45), major gap junctional proteins in the pre- and peri-implantation embryo. We generated Cx43−/−Cx45−/− embryos by Cx43+/−Cx45+/− intercrossing, because mice deficient in Cx43 (Cx43−/−) exhibit perinatal lethality and those deficient in Cx45 (Cx45−/−) exhibit early embryonic lethality. Wild-type, Cx43−/−, Cx45−/−, and Cx43−/−Cx45−/− blastocysts all showed similar outgrowths in in vitro culture. Moreover, Cx43−/−Cx45−/− embryos were obtained at the expected Mendelian ratio up to embryonic day 9.5, when the Cx45−/− mutation proved lethal. The Cx43−/−Cx45−/− embryos seemed to have no additional developmental abnormalities in comparison with the single knockout strains. Thus, pre- and peri-implantation development does not require Cx43 and Cx45. Other gap junctional proteins are expressed around these stages and these may compensate for the lack of Cx43 and Cx45.
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Nishii K, Shibata Y, Kobayashi Y. Connexin mutant embryonic stem cells and human diseases. World J Stem Cells 2014; 6:571-578. [PMID: 25426253 PMCID: PMC4178256 DOI: 10.4252/wjsc.v6.i5.571] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 09/11/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Intercellular communication via gap junctions allows cells within multicellular organisms to share small molecules. The effect of such interactions has been elucidated using mouse gene knockout strategies. Although several mutations in human gap junction-encoding connexin (Cx) have been described, Cx mutants in mice do not always recapitulate the human disease. Among the 20 mouse Cxs, Cx26, Cx43, and Cx45 play roles in early cardiac or placental development, and disruption of the genes results in lethality that hampers further analyses. Embryonic stem cells (ESCs) that lack Cx43 or Cx45 have made analysis feasible in both in vitro differentiated cell cultures and in vivo chimeric tissues. The success of mouse ESCs studies is leading to the use of induced pluripotent stem cells to learn more about the pathogenesis of human Cx diseases. This review summarizes the current status of mouse Cx disruption models and ESC differentiation studies, and discusses their implication for understanding human Cx diseases.
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Nielsen MS, Axelsen LN, Sorgen PL, Verma V, Delmar M, Holstein-Rathlou NH. Gap junctions. Compr Physiol 2013; 2:1981-2035. [PMID: 23723031 DOI: 10.1002/cphy.c110051] [Citation(s) in RCA: 313] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gap junctions are essential to the function of multicellular animals, which require a high degree of coordination between cells. In vertebrates, gap junctions comprise connexins and currently 21 connexins are known in humans. The functions of gap junctions are highly diverse and include exchange of metabolites and electrical signals between cells, as well as functions, which are apparently unrelated to intercellular communication. Given the diversity of gap junction physiology, regulation of gap junction activity is complex. The structure of the various connexins is known to some extent; and structural rearrangements and intramolecular interactions are important for regulation of channel function. Intercellular coupling is further regulated by the number and activity of channels present in gap junctional plaques. The number of connexins in cell-cell channels is regulated by controlling transcription, translation, trafficking, and degradation; and all of these processes are under strict control. Once in the membrane, channel activity is determined by the conductive properties of the connexin involved, which can be regulated by voltage and chemical gating, as well as a large number of posttranslational modifications. The aim of the present article is to review our current knowledge on the structure, regulation, function, and pharmacology of gap junctions. This will be supported by examples of how different connexins and their regulation act in concert to achieve appropriate physiological control, and how disturbances of connexin function can lead to disease.
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Affiliation(s)
- Morten Schak Nielsen
- Department of Biomedical Sciences and The Danish National Research Foundation Centre for Cardiac Arrhythmia, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Verheule S, Kaese S. Connexin diversity in the heart: insights from transgenic mouse models. Front Pharmacol 2013; 4:81. [PMID: 23818881 PMCID: PMC3694209 DOI: 10.3389/fphar.2013.00081] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 06/04/2013] [Indexed: 11/13/2022] Open
Abstract
Cardiac conduction is mediated by gap junction channels that are formed by connexin (Cx) protein subunits. The connexin family of proteins consists of more than 20 members varying in their biophysical properties and ability to combine with other connexins into heteromeric gap junction channels. The mammalian heart shows regional differences both in connexin expression profile and in degree of electrical coupling. The latter reflects functional requirements for conduction velocity which needs to be low in the sinoatrial and atrioventricular nodes and high in the ventricular conduction system. Over the past 20 years knowledge of the biology of gap junction channels and their role in the genesis of cardiac arrhythmias has increased enormously. This review focuses on the insights gained from transgenic mouse models. The mouse heart expresses Cx30, 30.2, 37, 40, 43, 45, and 46. For these connexins a variety of knock-outs, heart-specific knock-outs, conditional knock-outs, double knock-outs, knock-ins and overexpressors has been studied. We discuss the cardiac phenotype in these models and compare Cx expression between mice and men. Mouse models have enhanced our understanding of (patho)-physiological implications of Cx diversity in the heart. In principle connexin-specific modulation of electrical coupling in the heart represents an interesting treatment strategy for cardiac arrhythmias and conduction disorders.
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Affiliation(s)
- Sander Verheule
- Department of Physiology, Faculty of Medicine, Maastricht University Maastricht, Netherlands
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Frank M, Wirth A, Andrié RP, Kreuzberg MM, Dobrowolski R, Seifert G, Offermanns S, Nickenig G, Willecke K, Schrickel JW. Connexin45 Provides Optimal Atrioventricular Nodal Conduction in the Adult Mouse Heart. Circ Res 2012; 111:1528-38. [DOI: 10.1161/circresaha.112.270561] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Rationale:
The gap junctional protein connexin (Cx) 45 is strongly expressed in the early embryonic myocardium. In the adult hearts of mice and humans, the expression mainly is restricted to the cardiac conduction system. Cx45 plays an essential role for development and function of the embryonic heart because general and cardiomyocyte-directed deficiencies of Cx45 in mice lead to embryonic lethality attributable to morphological and functional cardiovascular defects. The function of Cx45 in the adult mouse has not yet been cleared.
Objective:
To clarify the function of Cx45 in the adult mouse heart.
Methods and Results:
To circumvent the embryonic lethality resulting from Cx45 deficiency, mice were generated in which deletion of Cx45 specifically was induced in cardiomyocytes of adult mice. These Cx45-deficient mice were viable but showed a decrease in atrioventricular nodal conductivity. In addition, the Cx30.2 protein that is coexpressed with Cx45 in the cardiac conduction system was posttranscriptionally reduced by 70% in mutant hearts. Furthermore, deletion of both Cx45 and Cx30.2 resulted in viable mice that, however, showed stronger impairment of atrioventricular nodal conduction than the single Cx45-deficient mice.
Conclusions:
Cx45 is required for optimal impulse propagation in the atrioventricular node and stabilizes the level of the coexpressed Cx30.2 protein in the adult mouse heart. In contrast to the embryo, Cx45 is not essential for the viability of adult mice.
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Affiliation(s)
- Marina Frank
- From the LIMES-Institute, Molecular Genetics (M.F., M.M.K., R.D., K.W.) and Institute of Cellular Neurosciences (G.S.), University of Bonn, Bonn, Germany; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (A.W., S.O.); and Department of Medicine-Cardiology, University Hospital Bonn, Bonn, Germany (R.P.A., G.N., J.W.S.)
| | - Angela Wirth
- From the LIMES-Institute, Molecular Genetics (M.F., M.M.K., R.D., K.W.) and Institute of Cellular Neurosciences (G.S.), University of Bonn, Bonn, Germany; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (A.W., S.O.); and Department of Medicine-Cardiology, University Hospital Bonn, Bonn, Germany (R.P.A., G.N., J.W.S.)
| | - René P. Andrié
- From the LIMES-Institute, Molecular Genetics (M.F., M.M.K., R.D., K.W.) and Institute of Cellular Neurosciences (G.S.), University of Bonn, Bonn, Germany; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (A.W., S.O.); and Department of Medicine-Cardiology, University Hospital Bonn, Bonn, Germany (R.P.A., G.N., J.W.S.)
| | - Maria M. Kreuzberg
- From the LIMES-Institute, Molecular Genetics (M.F., M.M.K., R.D., K.W.) and Institute of Cellular Neurosciences (G.S.), University of Bonn, Bonn, Germany; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (A.W., S.O.); and Department of Medicine-Cardiology, University Hospital Bonn, Bonn, Germany (R.P.A., G.N., J.W.S.)
| | - Radoslaw Dobrowolski
- From the LIMES-Institute, Molecular Genetics (M.F., M.M.K., R.D., K.W.) and Institute of Cellular Neurosciences (G.S.), University of Bonn, Bonn, Germany; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (A.W., S.O.); and Department of Medicine-Cardiology, University Hospital Bonn, Bonn, Germany (R.P.A., G.N., J.W.S.)
| | - Gerald Seifert
- From the LIMES-Institute, Molecular Genetics (M.F., M.M.K., R.D., K.W.) and Institute of Cellular Neurosciences (G.S.), University of Bonn, Bonn, Germany; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (A.W., S.O.); and Department of Medicine-Cardiology, University Hospital Bonn, Bonn, Germany (R.P.A., G.N., J.W.S.)
| | - Stefan Offermanns
- From the LIMES-Institute, Molecular Genetics (M.F., M.M.K., R.D., K.W.) and Institute of Cellular Neurosciences (G.S.), University of Bonn, Bonn, Germany; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (A.W., S.O.); and Department of Medicine-Cardiology, University Hospital Bonn, Bonn, Germany (R.P.A., G.N., J.W.S.)
| | - Georg Nickenig
- From the LIMES-Institute, Molecular Genetics (M.F., M.M.K., R.D., K.W.) and Institute of Cellular Neurosciences (G.S.), University of Bonn, Bonn, Germany; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (A.W., S.O.); and Department of Medicine-Cardiology, University Hospital Bonn, Bonn, Germany (R.P.A., G.N., J.W.S.)
| | - Klaus Willecke
- From the LIMES-Institute, Molecular Genetics (M.F., M.M.K., R.D., K.W.) and Institute of Cellular Neurosciences (G.S.), University of Bonn, Bonn, Germany; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (A.W., S.O.); and Department of Medicine-Cardiology, University Hospital Bonn, Bonn, Germany (R.P.A., G.N., J.W.S.)
| | - Jan W. Schrickel
- From the LIMES-Institute, Molecular Genetics (M.F., M.M.K., R.D., K.W.) and Institute of Cellular Neurosciences (G.S.), University of Bonn, Bonn, Germany; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (A.W., S.O.); and Department of Medicine-Cardiology, University Hospital Bonn, Bonn, Germany (R.P.A., G.N., J.W.S.)
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Abstract
The structure and functioning of the atrioventricular (AV) node has remained mysterious owing to its high degree of complexity. In this review article, we integrate advances in knowledge regarding connexin expression in the AV node. Complex patterning of 4 different connexin isoforms with single channel conductances ranging from ultralow to high explains the dual pathway electrophysiology of the AV node, the presence of 2 nodal extensions, longitudinal dissociation in the penetrating bundle, and, most importantly, how the AV node maintains slow conduction between the atria and the ventricles. It is shown that the complex patterning of connexins is the consequence of the embryonic development of the cardiac conduction system. Finally, it is argued that connexin dysregulation may be responsible for AV node dysfunction.
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Affiliation(s)
- Ian P Temple
- Institute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, 46 Grafton St, Manchester, UK
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Schrickel JW, Lickfett L, Lewalter T, Tiemann K, Nickenig G, Baba H, Heusch G, Schulz R, Levkau B. Cardiomyocyte-specific deletion of survivin causes global cardiac conduction defects. Basic Res Cardiol 2012; 107:299. [DOI: 10.1007/s00395-012-0299-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 08/22/2012] [Accepted: 09/04/2012] [Indexed: 11/28/2022]
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Kaese S, Verheule S. Cardiac electrophysiology in mice: a matter of size. Front Physiol 2012; 3:345. [PMID: 22973235 PMCID: PMC3433738 DOI: 10.3389/fphys.2012.00345] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Accepted: 08/09/2012] [Indexed: 12/27/2022] Open
Abstract
Over the last decade, mouse models have become a popular instrument for studying cardiac arrhythmias. This review assesses in which respects a mouse heart is a miniature human heart, a suitable model for studying mechanisms of cardiac arrhythmias in humans and in which respects human and murine hearts differ. Section I considers the issue of scaling of mammalian cardiac (electro) physiology to body mass. Then, we summarize differences between mice and humans in cardiac activation (section II) and the currents underlying the action potential in the murine working myocardium (section III). Changes in cardiac electrophysiology in mouse models of heart disease are briefly outlined in section IV, while section V discusses technical considerations pertaining to recording cardiac electrical activity in mice. Finally, section VI offers general considerations on the influence of cardiac size on the mechanisms of tachy-arrhythmias.
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Affiliation(s)
- Sven Kaese
- Division of Experimental and Clinical Electrophysiology, Department of Cardiology and Angiology, University Hospital Münster Münster, Germany
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17
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Kim KH, Rosen A, Bruneau BG, Hui CC, Backx PH. Iroquois homeodomain transcription factors in heart development and function. Circ Res 2012; 110:1513-24. [PMID: 22628575 DOI: 10.1161/circresaha.112.265041] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Numerous cardiac transcription factors play overlapping roles in both the specification and proliferation of the cardiac tissues and chambers during heart development. It has become increasingly apparent that cardiac transcription factors also play critical roles in the regulation of expression of many functional genes in the prenatal and postnatal hearts. Accordingly, mutations of cardiac transcription factors cannot only result in congenital heart defects but also alter heart function thereby predisposing to heart disease and cardiac arrhythmias. In this review, we summarize the roles of Iroquois homeobox (Irx) family of transcription factors in heart development and function. In all, 6 Irx genes are expressed with distinct and overlapping patterns in the mammalian heart. Studies in several animal models demonstrate that Irx genes are important for the establishment of ventricular chamber properties, the ventricular conduction system, as well as heterogeneity of the ventricular repolarization. The molecular mechanisms by which Irx proteins regulate gene expression and the clinical relevance of Irx functions in the heart are discussed.
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Affiliation(s)
- Kyoung-Han Kim
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
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18
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Tuomi JM, Tyml K, Jones DL. Atrial tachycardia/fibrillation in the connexin 43 G60S mutant (Oculodentodigital dysplasia) mouse. Am J Physiol Heart Circ Physiol 2011; 300:H1402-11. [PMID: 21239638 DOI: 10.1152/ajpheart.01094.2010] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Atrial fibrillation (AF), the most common cardiac arrhythmia seen in general practice, can be promoted by conduction slowing. Cardiac impulse conduction depends on gap junction channels, which are composed of connexins (Cxs). While atrial Cx40 and Cx43 are equally expressed, AF studies have primarily focused on Cx40 reductions. The G60S Cx43 mutant (Cx43(G60S/+)) mouse model of Oculodentodigital dysplasia has a 60% reduction in Cx43 in the atria. Cx43(G60S/+) mice were compared with Cx40-deficient (Cx40(-/-)) mice to determine the role of Cxs in atrial tachycardia/fibrillation (AT/F). Intracardiac electrophysiological studies were done in 6-mo-old male C57BL/6 Cx43(G60S/+) mutant, littermate (Cx43(+/+)), Cx40(-/-), and C57BL/6 wild-type (WT) mice. AT/F induction used an extra stimulus during sinus rhythm, programmed electrical stimulation, or burst pacing (1-ms pulses, 50-Hz, 400-ms train) in the absence and presence of carbachol (CCh). Atrial effective refractory periods did not differ between strains. Cx43(G60S/+) mice were more susceptible to induction of sustained AT/F (duration >2 min, 9 of 12; maximum >35 min) compared with Cx43(+/+) mice (3 of 11; χ(2) = 5.24; P = 0.02). CCh enhanced sustained AT/F susceptibility in WT (from 1 of 12 without, to 7 of 10 with CCh; χ(2) = 8.98; P < 0.01) but not in Cx40(-/-) mice (1 of 13 without vs. 2 of 9 with CCh; χ(2) = 0.95; P = NS). The pattern of epicardial recordings during AT/F in Cx43(G60S/+) mice was left preceding right, with left atrial fractionated activation patterns consistent with clinical observations of AF. In conclusions, while Cx43(G60S/+) mice had severe AT/F, Cx40(-/-) mice were resistant to CCh-induced AT/F.
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Affiliation(s)
- Jari M Tuomi
- Department of Physiology and Pharmacology, University of Western Ontario, London, Canada
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19
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Rentschler S, Harris BS, Kuznekoff L, Jain R, Manderfield L, Lu MM, Morley GE, Patel VV, Epstein JA. Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways. J Clin Invest 2011; 121:525-33. [PMID: 21266778 DOI: 10.1172/jci44470] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2010] [Accepted: 11/01/2010] [Indexed: 11/17/2022] Open
Abstract
Ventricular preexcitation, which characterizes Wolff-Parkinson-White syndrome, is caused by the presence of accessory pathways that can rapidly conduct electrical impulses from atria to ventricles, without the intrinsic delay characteristic of the atrioventricular (AV) node. Preexcitation is associated with an increased risk of tachyarrhythmia, palpitations, syncope, and sudden death. Although the pathology and electrophysiology of preexcitation syndromes are well characterized, the developmental mechanisms are poorly understood, and few animal models that faithfully recapitulate the human disorder have been described. Here we show that activation of Notch signaling in the developing myocardium of mice can produce fully penetrant accessory pathways and ventricular preexcitation. Conversely, inhibition of Notch signaling in the developing myocardium resulted in a hypoplastic AV node, with specific loss of slow-conducting cells expressing connexin-30.2 (Cx30.2) and a resulting loss of physiologic AV conduction delay. Taken together, our results suggest that Notch regulates the functional maturation of AV canal embryonic myocardium during the development of the specialized conduction system. Our results also show that ventricular preexcitation can arise from inappropriate patterning of the AV canal-derived myocardium.
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Affiliation(s)
- Stacey Rentschler
- Department of Cell and Developmental Biology and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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20
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Gros D, Théveniau-Ruissy M, Bernard M, Calmels T, Kober F, Söhl G, Willecke K, Nargeot J, Jongsma HJ, Mangoni ME. Connexin 30 is expressed in the mouse sino-atrial node and modulates heart rate. Cardiovasc Res 2010; 85:45-55. [PMID: 19679680 DOI: 10.1093/cvr/cvp280] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
AIMS This study aimed at characterizing expression and the functional role of the Gjb6 gene, encoding for connexin 30 (Cx30) protein, in the adult mouse heart. METHODS AND RESULTS The expression of the Gjb6 gene in the mouse heart was investigated by RT-PCR and sequencing of amplified cDNA fragments. The sites of Gjb6 expression were identified in the adult heart using transgenic mice with reporter genes (Cx30(LacZ/LacZ) and Cx30(LacZ/LacZ)/Cx40(EGFP/EGFP) mice), as well as anti-HCN4 (hyperpolarization activated cyclic nucleotide-gated potassium channel 4) or anti-connexin antibodies. Cine-magnetic resonance imaging and telemetric ECG recordings were used to evaluate the impact of Cx30 deficiency on cardiac physiology. Gjb6 was shown to be expressed in the sinoatrial (SA) node of the adult mouse heart. Eighty from 100 nuclei on average were LacZ-positive in the SA node of Cx30(LacZ/LacZ) mice. No significant LacZ expression was seen in other cardiac tissues. Cx30 protein was identified in low abundance in the SA node of wild-type mice, as indicated by immunofluorescence experiments. Telemetric ECG recordings indicated that Cx30-deficient mice displayed a mean daily heart rate (HR) that was 9% faster than that measured in control mice (572 +/- 38 b.p.m. vs. 524 +/- 23, P < 0.05). This moderate tachycardia was still observed after inhibition of the autonomic nervous system, demonstrating that Cx30 deficiency resulted in changes in the intrinsic electrical properties of the SA node. Consistent with this hypothesis, Cx30(LacZ/LacZ) displayed a significant reduction of SDNN (standard deviation of the interbeat interval) compared with control mice. Increase of both the cardiac index (20%) and the end-diastolic volume to body weight ratio (16%) with no deficiency in ejection fraction or stroke volume were observed in mutant mice. An increase in cardiac index was interpreted as being a direct consequence of high HR, whereas large end-diastolic volume may be an indirect consequence of prolonged high HR. CONCLUSION Cx30 is functionally expressed, in low abundance, in the SA node of the adult mouse heart where it participates in HR regulation.
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Affiliation(s)
- Daniel Gros
- Institut de Biologie du Développement de Marseille-Luminy, Université de la Méditerranée, Marseille, France.
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Munshi NV, McAnally J, Bezprozvannaya S, Berry JM, Richardson JA, Hill JA, Olson EN. Cx30.2 enhancer analysis identifies Gata4 as a novel regulator of atrioventricular delay. Development 2009; 136:2665-74. [PMID: 19592579 DOI: 10.1242/dev.038562] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The cardiac conduction system comprises a specialized tract of electrically coupled cardiomyocytes responsible for impulse propagation through the heart. Abnormalities in cardiac conduction are responsible for numerous forms of cardiac arrhythmias, but relatively little is known about the gene regulatory mechanisms that control the formation of the conduction system. We demonstrate that a distal enhancer for the connexin 30.2 (Cx30.2, also known as Gjd3) gene, which encodes a gap junction protein required for normal atrioventricular (AV) delay in mice, is necessary and sufficient to direct expression to the developing AV conduction system (AVCS). Moreover, we show that this enhancer requires Tbx5 and Gata4 for proper expression in the conduction system, and Gata4(+/-) mice have short PR intervals indicative of accelerated AV conduction. Thus, our results implicate Gata4 in conduction system function and provide a clearer understanding of the transcriptional pathways that impact normal AV delay.
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Affiliation(s)
- Nikhil V Munshi
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
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22
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Jansen JA, van Veen TAB, de Bakker JMT, van Rijen HVM. Cardiac connexins and impulse propagation. J Mol Cell Cardiol 2009; 48:76-82. [PMID: 19729017 DOI: 10.1016/j.yjmcc.2009.08.018] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2009] [Revised: 07/29/2009] [Accepted: 08/21/2009] [Indexed: 12/15/2022]
Abstract
Gap junctions form the intercellular pathway for cell-to-cell transmission of the cardiac impulse from its site of origin, the sinoatrial node, along the atria, the atrioventricular conduction system to the ventricular myocardium. The component parts of gap junctions are proteins called connexins (Cx), of which three main isoforms are found in the conductive and working myocardial cells: Cx40, Cx43, and Cx45. These isoforms are regionally expressed in the heart, which suggests a specific role or function of a specific connexin in a certain part of the heart. Using genetically modified mice, the function of these connexins in the different parts of the heart have been assessed in the past years. This review will follow the cardiac impulse on its path through the heart and recapitulate the role of the different connexins in the different cardiac compartments.
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Affiliation(s)
- John A Jansen
- Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, The Netherlands
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