Anisotropic Cardiac Conduction

Anisotropy is the property of directional dependence. In cardiac tissue, conduction velocity is anisotropic and its orientation is determined by myocyte direction. Cell shape and size, excitability, myocardial fibrosis, gap junction distribution and function are all considered to contribute to anisotropic conduction. In disease states, anisotropic conduction may be enhanced, and is implicated, in the genesis of pathological arrhythmias. The principal mechanism responsible for enhanced anisotropy in disease remains uncertain. Possible contributors include changes in cellular excitability, changes in gap junction distribution or function and cellular uncoupling through interstitial fibrosis. It has recently been demonstrated that myocyte orientation may be identified using diffusion tensor magnetic resonance imaging in explanted hearts, and multisite pacing protocols have been proposed to estimate myocyte orientation and anisotropic conduction in vivo. These tools have the potential to contribute to the understanding of the role of myocyte disarray and anisotropic conduction in arrhythmic states.

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Biophysical stimulation for in vitro engineering of functional cardiac tissues

Clinical Science ◽

10.1042/cs20170055 ◽

2017 ◽

Vol 131 (13) ◽

pp. 1393-1404 ◽

Cited By ~ 14

Author(s):

Anastasia Korolj ◽

Erika Yan Wang ◽

Robert A. Civitarese ◽

Milica Radisic

Keyword(s):

Cardiac Tissue ◽

Culture Media ◽

Culture Conditions ◽

Lineage Specification ◽

Cardiac Tissues ◽

Cardiac Lineage ◽

And Function ◽

Tissue Models

Engineering functional cardiac tissues remains an ongoing significant challenge due to the complexity of the native environment. However, our growing understanding of key parameters of the in vivo cardiac microenvironment and our ability to replicate those parameters in vitro are resulting in the development of increasingly sophisticated models of engineered cardiac tissues (ECT). This review examines some of the most relevant parameters that may be applied in culture leading to higher fidelity cardiac tissue models. These include the biochemical composition of culture media and cardiac lineage specification, co-culture conditions, electrical and mechanical stimulation, and the application of hydrogels, various biomaterials, and scaffolds. The review will also summarize some of the recent functional human tissue models that have been developed for in vivo and in vitro applications. Ultimately, the creation of sophisticated ECT that replicate native structure and function will be instrumental in advancing cell-based therapeutics and in providing advanced models for drug discovery and testing.

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Zinc Modulation of Hemi-Gap-Junction Channel Currents in Retinal Horizontal Cells

Journal of Neurophysiology ◽

10.1152/jn.90581.2008 ◽

2009 ◽

Vol 101 (4) ◽

pp. 1774-1780 ◽

Cited By ~ 21

Author(s):

Ziyi Sun ◽

Dao-Qi Zhang ◽

Douglas G. McMahon

Keyword(s):

Gap Junction ◽

Inhibitory Action ◽

Divalent Cations ◽

Horizontal Cells ◽

Visual Signals ◽

Histidine Residues ◽

Gap Junction Channel ◽

And Function ◽

Channel Currents

Hemi-gap-junction (HGJ) channels of retinal horizontal cells (HCs) function as transmembrane ion channels that are modulated by voltage and calcium. As an endogenous retinal neuromodulator, zinc, which is coreleased with glutamate at photoreceptor synapses, plays an important role in shaping visual signals by acting on postsynaptic HCs in vivo. To understand more fully the regulation and function of HC HGJ channels, we examined the effect of Zn2+ on HGJ channel currents in bass retinal HCs. Hemichannel currents elicited by depolarization in Ca2+-free medium and in 1 mM Ca2+ medium were significantly inhibited by extracellular Zn2+. The inhibition by Zn2+ of hemichannel currents was dose dependent with a half-maximum inhibitory concentration of 37 μM. Compared with other divalent cations, Zn2+ exhibited higher inhibitory potency, with the order being Zn2+ > Cd2+ ≈ Co2+ > Ca2+ > Ba2+ > Mg2+. Zn2+ and Ca2+ were found to modulate HGJ channels independently in additivity experiments. Modification of histidine residues with N-bromosuccinimide suppressed the inhibitory action of Zn2+, whereas modification of cysteine residues had no significant effect on Zn2+ inhibition. Taken together, these results suggest that zinc acts on HGJ channels in a calcium-independent way and that histidine residues on the extracellular domain of HGJ channels mediate the inhibitory action of zinc.

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Cx50 requires an intact PDZ-binding motif and ZO-1 for the formation of functional intercellular channels

Molecular Biology of the Cell ◽

10.1091/mbc.e11-05-0438 ◽

2011 ◽

Vol 22 (23) ◽

pp. 4503-4512 ◽

Cited By ~ 18

Author(s):

Zhifang Chai ◽

Daniel A. Goodenough ◽

David L. Paul

Keyword(s):

Gap Junction ◽

Hela Cells ◽

Pdz Domain ◽

Cell Communication ◽

Normal Function ◽

Scaffolding Protein ◽

Binding Motif ◽

Interacting Protein ◽

And Function

The three connexins expressed in the ocular lens each contain PDZ domain–binding motifs directing a physical association with the scaffolding protein ZO-1, but the significance of the interaction is unknown. We found that Cx50 with PDZ-binding motif mutations did not form gap junction plaques or induce cell–cell communication in HeLa cells, whereas the addition of a seven–amino acid PDZ-binding motif restored normal function to Cx50 lacking its entire C-terminal cytoplasmic domain. C-Terminal deletion had a similar although weaker effect on Cx46 but little if any effect on targeting and function of Cx43. Furthermore, small interfering RNA knockdown of ZO-1 completely inhibited the formation of gap junctions by wild-type Cx50 in HeLa cells. Thus both a PDZ-binding motif and ZO-1 are necessary for Cx50 intercellular channel formation in HeLa cells. Knock-in mice expressing Cx50 with a PDZ-binding motif mutation phenocopied Cx50 knockouts. Furthermore, differentiating lens fibers in the knock-in displayed extensive intracellular Cx50, whereas plaques in mature fibers contained only Cx46. Thus normal Cx50 function in vivo also requires an intact PDZ domain–binding motif. This is the first demonstration of a connexin-specific requirement for a connexin-interacting protein in gap junction assembly.

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Asymmetry of an intracellular scaffold at vertebrate electrical synapses

10.1101/173955 ◽

2017 ◽

Author(s):

Audrey J Marsh ◽

Jennifer Carlisle Michel ◽

Anisha P Adke ◽

Emily L Heckman ◽

Adam C Miller

Keyword(s):

Gap Junction ◽

Synapse Formation ◽

Neural Circuit ◽

Electrical Synapse ◽

Electrical Synapses ◽

Gap Junction Channels ◽

Junction Protein ◽

Chemical Synapses ◽

And Function

AbstractNeuronal synaptic connections are electrical or chemical and together are essential to dynamically defining neural circuit function. While chemical synapses are well known for their biochemical complexity, electrical synapses are often viewed as comprised solely of neuronal gap junction channels that allow direct ionic and metabolic communication. However, associated with the gap junction channels are structures observed by electron microscopy called the Electrical Synapse Density (ESD). The ESD has been suggested to be critical for the formation and function of the electrical synapse, yet the biochemical makeup of these structures is poorly understood. Here we find that electrical synapse formation in vivo requires an intracellular scaffold called Tight Junction Protein 1b (Tjp1b). Tjp1b is localized to electrical synapses where it is required for the stabilization of the gap junction channels and for electrical synapse function. Strikingly, we find that Tjp1b protein localizes and functions asymmetrically, exclusively on the postsynaptic side of the synapse. Our findings support a novel model in which there is molecular asymmetry at the level of the intracellular scaffold that is required for building the electrical synapse. ESD molecular asymmetries may be a fundamental motif of all nervous systems and could support functional asymmetry at the electrical synapse.

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Electrophysiological phenotyping in genetically engineered mice

Physiological Genomics ◽

10.1152/physiolgenomics.00183.2002 ◽

2003 ◽

Vol 13 (3) ◽

pp. 207-216 ◽

Cited By ~ 24

Author(s):

Charles I. Berul

Keyword(s):

Molecular Mechanisms ◽

Heart Defects ◽

Gene Mutations ◽

Genetically Engineered ◽

Experimental Methodology ◽

Cardiac Conduction ◽

Disease States ◽

Genetically Engineered Mice ◽

Study Techniques

Advances in transgene and gene targeting technology have enabled sophisticated manipulation of the mouse genome, providing important insights into the molecular mechanisms underlying cardiac conduction, arrhythmogenesis, and sudden cardiac death. The mouse is currently the principal mammalian model for studying biological processes, particularly related to cardiac pathophysiology. Murine models have been engineered harboring gene mutations leading to inherited structural and electrical disorders of the heart due to transcription factor mutations, connexin protein defects, and G protein and ion channelopathies. These mutations lead to phenotypes reminiscent of human clinical disease states including congenital heart defects, cardiomyopathies, and long-QT syndrome, creating models of human electrophysiological disease. Functional analyses of the underlying molecular mechanisms of resultant phenotypes require appropriate and sophisticated experimental methodology. This paper reviews current in vivo murine electrophysiology study techniques and genetic mouse models pertinent to human arrhythmia disorders.

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Abstract 253: HSPB7 is Required for Maintaining the Intercalated Disc Structure to Prevent Cardiac Conduction System Failure in Mouse

Circulation Research ◽

10.1161/res.121.suppl_1.253 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Wern-Chir Liao ◽

Liang-Yi Juo ◽

Yen-Hui Chen ◽

Yu-Ting Yan

Keyword(s):

Heart Failure ◽

Gap Junction ◽

Connexin 43 ◽

Adherens Junction ◽

Small Heat Shock Protein ◽

Cardiac Conduction ◽

Nucleotide Polymorphisms ◽

Intercalated Disc ◽

Junction Protein ◽

And Function

HSPB7 is belonged to small heat-shock protein (HSPB) family and considered to function as a co-chaperone, which prevents protein aggregation and maintains protein structure. Single-nucleotide polymorphisms of HSPB7 associated with sporadic cardiomyopathy and heart failure have been identified in human patients. Additionally, HSPB7 is constitutively expressed in heart and rapidly increased in blood plasma after myocardial infarction, suggesting a functional role in the heart. In this study, we found that HSPB7 is highly colocalized with N-cadherin during the assembly and maturation of intercalated disc, suggesting that HSPB7 may involve in organizing and maintaining the cardiac cytoarchitecture. To elucidate the physiological function of HSPB7 in the adult heart, we generated a cardiac-specific inducible HSPB7 knockout mouse. Ablation of HSPB7 in the cardiomyocyte rapidly leads to heart failure, abnormal conduction properties and sudden arrhythmias death. Loss of HSPB7 did not cause significant changes in the organization of contractile proteins in sarcomeres, whereas severe abnormality in the intercalated disc was detected. The expression of connexin 43, a gap-junction protein located at the intercalated disc, was downregulated in HSPB7 knockout cardiomyocytes. Mislocalizations of desmoplakin (desmosomal proteins), and N-cadherin (adherens junction proteins) were also observed in the HSPB7 CKO hearts. Furthermore, filamin C, the interaction protein of HSPB7, was mislocalized and aggregated in HSPB7 mutant cardiomyocytes. The expressivity of the phenotype in the HSPB7 CKO mice is similar to human arrhythmogenic cardiomyopathy patients. Conclusively, we provide the first study characterizing HSPB7 as an intercalated disc protein. Our findings demonstrate that HSPB7 plays an essential role to maintain the structure and function of gap-junction complexes and intercalated disc and has vital implications for human heart disease.

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Role of diet fat in subcellular structure and function

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y85-094 ◽

1985 ◽

Vol 63 (5) ◽

pp. 546-556 ◽

Cited By ~ 103

Author(s):

M. T. Clandinin ◽

C. J. Field ◽

K. Hargreaves ◽

L. Morson ◽

E. Zsigmond

Keyword(s):

Plasma Membrane ◽

Cardiac Tissue ◽

Dietary Lipid ◽

Head Group ◽

Polar Head Group ◽

Mitochondrial Atpase ◽

Membrane Composition ◽

Lipid Environment ◽

And Function

Current concepts of the biomembrane will be extrapolated to membranes of homeotherms to illustrate the influence of the nature of dietary lipid in nutritionally complete diets on membrane polar head group content and fatty acid composition. Utilizing animal models, the controlling influence of dietary long chain fatty acids on major lipid constituents of the mitochondrial membrane in cardiac tissue, the plasma membrane of liver, and the synaptosomal membrane in brain can be demonstrated. Diet-induced alterations in membrane composition arc associated with demonstrable changes in the function of specific membrane proteins. To illustrate this relationship, the effect of diet on mitochondrial ATPase activity and on a hormone receptor-stimulated function in the plasma membrane of the liver will be discussed. These observations suggest that the diet fat modulates enzyme functions in vivo by changing the surrounding lipid environment in the membrane.

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Disturbances in White Matter Integrity in the Ultra-High-Risk Psychosis State—A Systematic Review

Journal of Clinical Medicine ◽

10.3390/jcm10112515 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2515

Author(s):

Katarzyna Waszczuk ◽

Katarzyna Rek-Owodziń ◽

Ernest Tyburski ◽

Monika Mak ◽

Błażej Misiak ◽

...

Keyword(s):

White Matter ◽

High Risk ◽

Diffusion Tensor ◽

Schizophrenia Spectrum Disorders ◽

Schizophrenia Spectrum ◽

Inferior Longitudinal Fasciculus ◽

Ultra High Risk ◽

Recent Developments ◽

And Function

Schizophrenia is a severe and disabling mental illness whose etiology still remains unclear. The available literature indicates that there exist white matter (WM) abnormalities in people with schizophrenia spectrum disorders. Recent developments in modern neuroimaging methods have enabled the identification of the structure, morphology, and function of the underlying WM fibers in vivo. The purpose of this paper is to review the existing evidence about WM abnormalities in individuals at ultra-high risk of psychosis (UHR) with the use of diffusion tensor imaging (DTI) available from the National Center for Biotechnology Information PubMed (Medline) and Health Source: Nursing/Academic Edition databases. Of 358 relevant articles identified, 25 papers published in the years 2008–2020 were ultimately included in the review. Most of them supported the presence of subtle aberrations in WM in UHR individuals, especially in the superior longitudinal fasciculus (SLF), the inferior longitudinal fasciculus (ILF), and the inferior fronto-occipital fasciculus (IFOF). These alterations may therefore be considered a promising neurobiological marker for the risk of psychosis. However, due to methodological discrepancies and the relative scarcity of evidence, further investigation is called for, especially into connectome analysis in UHR patients.

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Lung organoids: advances in generation and 3D-visualization

Histochemistry and Cell Biology ◽

10.1007/s00418-020-01955-w ◽

2021 ◽

Author(s):

Brian Cunniff ◽

Joseph E. Druso ◽

Jos L. van der Velden

Keyword(s):

Lung Function ◽

Ex Vivo ◽

3D Visualization ◽

Expression Patterns ◽

Cell Types ◽

Experimental Manipulation ◽

Molecular Response ◽

Disease States ◽

And Function

AbstractThe lung is comprised of more than 40 distinct cell types that support a complex 3-dimensional (3D) architecture that is required for efficient lung function. Loss of this proper architecture can accommodate and promote lung disease, highlighting researchers’ growing need to analyze lung structures in detail. Additionally, in vivo cellular and molecular response to chemical and physical signals, along with the recapitulation of gene-expression patterns, can be lost during the transition from complex 3D tissues to 2D cell culture systems. Therefore, technologies that allow for the investigation of lung function under normal and disease states utilizing the entirety of the lung architecture are required to generate a complete understanding of these processes. Airway cell-derived organoids that can recapitulate lung structure and function ex vivo while being amenable to experimental manipulation, have provided a new and exciting model system to investigate lung biology. In this perspective, we discuss emerging technologies for culturing lung-derived organoids, techniques to visualize organoids using high-resolution microscopy and the resulting information extracted from organoids supporting research focused on lung function and diseases.

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p53 regulates the cardiac transcriptome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1621436114 ◽

2017 ◽

Vol 114 (9) ◽

pp. 2331-2336 ◽

Cited By ~ 47

Author(s):

Tak W. Mak ◽

Ludger Hauck ◽

Daniela Grothe ◽

Filio Billia

Keyword(s):

Cardiac Tissue ◽

Acute Stress ◽

Gene Expression Signature ◽

Gene Clusters ◽

Biomechanical Stress ◽

Adult Mice ◽

Genome Wide ◽

Pathway Analyses ◽

And Function

The tumor suppressor Trp53 (p53) inhibits cell growth after acute stress by regulating gene transcription. The mammalian genome contains hundreds of p53-binding sites. However, whether p53 participates in the regulation of cardiac tissue homeostasis under normal conditions is not known. To examine the physiologic role of p53 in adult cardiomyocytes in vivo, Cre-loxP–mediated conditional gene targeting in adult mice was used. Genome-wide transcriptome analyses of conditional heart-specific p53 knockout mice were performed. Genome-wide annotation and pathway analyses of >5,000 differentially expressed transcripts identified many p53-regulated gene clusters. Correlative analyses identified >20 gene sets containing more than 1,000 genes relevant to cardiac architecture and function. These transcriptomic changes orchestrate cardiac architecture, excitation-contraction coupling, mitochondrial biogenesis, and oxidative phosphorylation capacity. Interestingly, the gene expression signature in p53-deficient hearts confers resistance to acute biomechanical stress. The data presented here demonstrate a role for p53, a previously unrecognized master regulator of the cardiac transcriptome. The complex contributions of p53 define a biological paradigm for the p53 regulator network in the heart under physiological conditions.

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