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Biomolecules
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Calcium Regulation in the Cardiac Cells
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Calcium Regulation in the Cardiac Cells

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 12142

Special Issue Editor

Dr. Chi Keung Lam

E-Mail Website
Guest Editor
Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
Interests: heart disease; calcium regulation; stress signalling; chaperone; proteasome

Special Issue Information

Dear Colleagues, 

From amplifying signals originating from a membrane receptor to coupling membrane excitation to muscle contraction, calcium is an essential second messenger in all mammalian cells. With its central roles in transcription factor activation, energy production in mitochondria, and subcellular vesicle functions, it is unquestionable that calcium dysregulation is a crucial factor in the development of cardiac disease. Despite the fact that the importance of calcium regulation in the heart is widely recognized, we are still lacking a complete understanding of how calcium is regulated in different subcellular compartments or cell types and how crosstalk between pathways or cells can be mediated. 

In this Special Issue of Biomolecules , “Calcium Regulation in the Cardiac Cells,“ we invite research papers and reviews reporting any breakthroughs on dissecting how calcium and its associated signaling pathways are regulated in cardiac cells in either physiological or pathological conditions. Furthermore, we encourage new findings on the use of small molecules, noncoding RNAs, exosomes, or any other cell-free substances to regulate calcium signaling in the heart as well. Lastly, we also welcome any reports on examining pre-existing medications with a novel mechanism of action related to calcium handling in cardiac cells. Cardiac cells are broadly defined as any cells residing within the heart, including fibroblasts, macrophages, endothelial cells, progenitor cells, etc. We will also consider reports utilizing cardiac-specific cells derived from stem cells as the modeling platform.

Dr. Chi Keung Lam
Guest Editor

Manuscript Submission Information

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

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

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

Keywords

  • calcium
  • calcium kinetics
  • calcium channels
  • signaling pathway
  • excitation-contraction coupling
  • contractility
  • endoplasmic and sarcoplasmic reticulum
  • cardiomyopathies
  • mitochondria
  • transcription
  • crosstalk

Published Papers (6 papers)

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20 pages, 29251 KiB  
Article
Characterization of Experimentally Observed Complex Interplay between Pulse Duration, Electrical Field Strength, and Cell Orientation on Electroporation Outcome Using a Time-Dependent Nonlinear Numerical Model
by Maria Scuderi, Janja Dermol-Černe, Tina Batista Napotnik, Sebastien Chaigne, Olivier Bernus, David Benoist, Daniel C. Sigg, Lea Rems and Damijan Miklavčič
Biomolecules 2023, 13(5), 727; https://doi.org/10.3390/biom13050727 - 23 Apr 2023
Cited by 5 | Viewed by 1465
Abstract
Electroporation is a biophysical phenomenon involving an increase in cell membrane permeability to molecules after a high-pulsed electric field is applied to the tissue. Currently, electroporation is being developed for non-thermal ablation of cardiac tissue to treat arrhythmias. Cardiomyocytes have been shown to [...] Read more.
Electroporation is a biophysical phenomenon involving an increase in cell membrane permeability to molecules after a high-pulsed electric field is applied to the tissue. Currently, electroporation is being developed for non-thermal ablation of cardiac tissue to treat arrhythmias. Cardiomyocytes have been shown to be more affected by electroporation when oriented with their long axis parallel to the applied electric field. However, recent studies demonstrate that the preferentially affected orientation depends on the pulse parameters. To gain better insight into the influence of cell orientation on electroporation with different pulse parameters, we developed a time-dependent nonlinear numerical model where we calculated the induced transmembrane voltage and pores creation in the membrane due to electroporation. The numerical results show that the onset of electroporation is observed at lower electric field strengths for cells oriented parallel to the electric field for pulse durations ≥10 µs, and cells oriented perpendicular for pulse durations ~100 ns. For pulses of ~1 µs duration, electroporation is not very sensitive to cell orientation. Interestingly, as the electric field strength increases beyond the onset of electroporation, perpendicular cells become more affected irrespective of pulse duration. The results obtained using the developed time-dependent nonlinear model are corroborated by in vitro experimental measurements. Our study will contribute to the process of further development and optimization of pulsed-field ablation and gene therapy in cardiac treatments. Full article
(This article belongs to the Special Issue Calcium Regulation in the Cardiac Cells)
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18 pages, 4071 KiB  
Article
Does Enhanced Structural Maturity of hiPSC-Cardiomyocytes Better for the Detection of Drug-Induced Cardiotoxicity?
by Dieter Van de Sande, Mohammadreza Ghasemi, Taylor Watters, Francis Burton, Ly Pham, Cristina Altrocchi, David J. Gallacher, Huarong Lu and Godfrey Smith
Biomolecules 2023, 13(4), 676; https://doi.org/10.3390/biom13040676 - 14 Apr 2023
Viewed by 1501
Abstract
Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are currently used following the Comprehensive in vitro Proarrhythmic Assay (CiPA) initiative and subsequent recommendations in the International Council for Harmonization (ICH) guidelines S7B and E14 Q&A, to detect drug-induced cardiotoxicity. Monocultures of hiPSC-CMs are [...] Read more.
Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are currently used following the Comprehensive in vitro Proarrhythmic Assay (CiPA) initiative and subsequent recommendations in the International Council for Harmonization (ICH) guidelines S7B and E14 Q&A, to detect drug-induced cardiotoxicity. Monocultures of hiPSC-CMs are immature compared to adult ventricular cardiomyocytes and might lack the native heterogeneous nature. We investigated whether hiPSC-CMs, treated to enhance structural maturity, are superior in detecting drug-induced changes in electrophysiology and contraction. This was achieved by comparing hiPSC-CMs cultured in 2D monolayers on the current standard (fibronectin matrix, FM), to monolayers on a coating known to promote structural maturity (CELLvo™ Matrix Plus, MM). Functional assessment of electrophysiology and contractility was made using a high-throughput screening approach involving the use of both voltage-sensitive fluorescent dyes for electrophysiology and video technology for contractility. Using 11 reference drugs, the response of the monolayer of hiPSC-CMs was comparable in the two experimental settings (FM and MM). The data showed no functionally relevant differences in electrophysiology between hiPSC-CMs in standard FM and MM, while contractility read-outs indicated an altered amplitude of contraction but not changes in time course. RNA profiling for cardiac proteins shows similarity of the RNA expression across the two forms of 2D culture, suggesting that cell-to-matrix adhesion differences may explain account for differences in contraction amplitude. The results support the view that hiPSC-CMs in both 2D monolayer FM and MM that promote structural maturity are equally effective in detecting drug-induced electrophysiological effects in functional safety studies. Full article
(This article belongs to the Special Issue Calcium Regulation in the Cardiac Cells)
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22 pages, 5558 KiB  
Article
Metabolic Maturation Exaggerates Abnormal Calcium Handling in a Lamp2 Knockout Human Pluripotent Stem Cell-Derived Cardiomyocyte Model of Danon Disease
by Robert J. Barndt, Qing Liu, Ying Tang, Michael P. Haugh, Jeffery Cui, Stephen Y. Chan and Haodi Wu
Biomolecules 2023, 13(1), 69; https://doi.org/10.3390/biom13010069 - 29 Dec 2022
Viewed by 2769
Abstract
Danon disease (DD) is caused by mutations of the gene encoding lysosomal-associated membrane protein type 2 (LAMP2), which lead to impaired autophagy, glycogen accumulation, and cardiac hypertrophy. However, it is not well understood why a large portion of DD patients develop [...] Read more.
Danon disease (DD) is caused by mutations of the gene encoding lysosomal-associated membrane protein type 2 (LAMP2), which lead to impaired autophagy, glycogen accumulation, and cardiac hypertrophy. However, it is not well understood why a large portion of DD patients develop arrhythmia and sudden cardiac death. In the current study, we generated LAMP2 knockout (KO) human iPSC-derived cardiomyocytes (CM), which mimic the LAMP2 dysfunction in DD heart. Morphologic analysis demonstrated the sarcomere disarrangement in LAMP2 KO CMs. In functional studies, LAMP2 KO CMs showed near-normal calcium handling at base level. However, treatment of pro-maturation medium (MM) exaggerated the disease phenotype in the KO cells as they exhibited impaired calcium recycling and increased irregular beating events, which recapitulates the pro-arrhythmia phenotypes of DD patients. Further mechanistic study confirmed that MM treatment significantly enhanced the autophagic stress in the LAMP2 KO CMs, which was accompanied by an increase of both cellular and mitochondrial reactive oxygen species (ROS) levels. Excess ROS accumulation in LAMP2 KO CMs resulted in the over-activation of calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) and arrhythmogenesis, which was partially rescued by the treatment of ROS scavenger. In summary, our study has revealed ROS induced CaMKIIδ overactivation as a key mechanism that promotes cardiac arrhythmia in DD patients. Full article
(This article belongs to the Special Issue Calcium Regulation in the Cardiac Cells)
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14 pages, 2831 KiB  
Article
A Large-Scale High-Throughput Screen for Modulators of SERCA Activity
by Philip A. Bidwell, Samantha L. Yuen, Ji Li, Kaja Berg, Robyn T. Rebbeck, Courtney C. Aldrich, Osha Roopnarine, Razvan L. Cornea and David D. Thomas
Biomolecules 2022, 12(12), 1789; https://doi.org/10.3390/biom12121789 - 30 Nov 2022
Cited by 5 | Viewed by 2812
Abstract
The sarco/endoplasmic reticulum Ca-ATPase (SERCA) is a P-type ion pump that transports Ca2+ from the cytosol into the endoplasmic/sarcoplasmic reticulum (ER/SR) in most mammalian cells. It is critically important in muscle, facilitating relaxation and enabling subsequent contraction. Increasing SERCA expression or specific [...] Read more.
The sarco/endoplasmic reticulum Ca-ATPase (SERCA) is a P-type ion pump that transports Ca2+ from the cytosol into the endoplasmic/sarcoplasmic reticulum (ER/SR) in most mammalian cells. It is critically important in muscle, facilitating relaxation and enabling subsequent contraction. Increasing SERCA expression or specific activity can alleviate muscle dysfunction, most notably in the heart, and we seek to develop small-molecule drug candidates that activate SERCA. Therefore, we adapted an NADH-coupled assay, measuring Ca-dependent ATPase activity of SERCA, to high-throughput screening (HTS) format, and screened a 46,000-compound library of diverse chemical scaffolds. This HTS platform yielded numerous hits that reproducibly alter SERCA Ca-ATPase activity, with few false positives. The top 19 activating hits were further tested for effects on both Ca-ATPase and Ca2+ transport, in both cardiac and skeletal SR. Nearly all hits increased Ca2+ uptake in both cardiac and skeletal SR, with some showing isoform specificity. Furthermore, dual analysis of both activities identified compounds with a range of effects on Ca2+-uptake and ATPase, which fit into distinct classifications. Further study will be needed to identify which classifications are best suited for therapeutic use. These results reinforce the need for robust secondary assays and criteria for selection of lead compounds, before undergoing HTS on a larger scale. Full article
(This article belongs to the Special Issue Calcium Regulation in the Cardiac Cells)
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15 pages, 3163 KiB  
Article
Right Ventricle Remodelling in Left-Sided Heart Failure in Rats: The Role of Calcium Signalling
by Aleksandra Paterek, Marta Oknińska, Michał Mączewski and Urszula Mackiewicz
Biomolecules 2022, 12(11), 1714; https://doi.org/10.3390/biom12111714 - 19 Nov 2022
Viewed by 1387
Abstract
Right ventricular dysfunction (RVD) can follow primary pulmonary diseases, but the most common cause of its development is left-sided heart failure (HF). RVD is associated with HF progression, increased risk of death and hospitalisation. The mechanism of right ventricle (RV) remodelling leading to [...] Read more.
Right ventricular dysfunction (RVD) can follow primary pulmonary diseases, but the most common cause of its development is left-sided heart failure (HF). RVD is associated with HF progression, increased risk of death and hospitalisation. The mechanism of right ventricle (RV) remodelling leading to RVD due to left-sided HF is not fully elucidated. Rats underwent LAD ligation to induce extensive left ventricle (LV) myocardial infarction (MI) and subsequent left-sided HF. Sham-operated animals served as controls. After 8 weeks of follow-up, the animals underwent LV and RV catheterisation, and systolic function and intracellular Ca2+ signalling were assessed in cardiomyocytes isolated from both ventricles. We demonstrated that rats with LV failure induced by extensive LV myocardial infarction also develop RV failure, leading to symptomatic biventricular HF, despite only mildly increased RV afterload. The contractility of RV cardiomyocytes was significantly increased, which could be related to increased amplitude of Ca2+ transient, preserved SERCA2a activity and reduced Ca2+ efflux via NCX1 and PMCA. Our study indicates that RV failure associated with post-MI LV failure in a rat model cannot be explained by a decline in cardiomyocyte function. This indicates that other factors may play a role here, pointing to the need for further research to better understand the biology of RV failure in order to ultimately develop therapies targeting the RV. Full article
(This article belongs to the Special Issue Calcium Regulation in the Cardiac Cells)
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9 pages, 939 KiB  
Brief Report
The ‘Reverse FDUF’ Mechanism of Atrial Excitation–Contraction Coupling Sustains Calcium Alternans—A Hypothesis
by Kathrin Banach and Lothar A. Blatter
Biomolecules 2023, 13(1), 7; https://doi.org/10.3390/biom13010007 - 20 Dec 2022
Cited by 1 | Viewed by 1477
Abstract
Cardiac calcium alternans is defined as beat-to-beat alternations of Ca transient (CaT) amplitude and has been linked to cardiac arrhythmia, including atrial fibrillation. We investigated the mechanism of atrial alternans in isolated rabbit atrial myocytes using high-resolution line scan confocal Ca imaging. Alternans [...] Read more.
Cardiac calcium alternans is defined as beat-to-beat alternations of Ca transient (CaT) amplitude and has been linked to cardiac arrhythmia, including atrial fibrillation. We investigated the mechanism of atrial alternans in isolated rabbit atrial myocytes using high-resolution line scan confocal Ca imaging. Alternans was induced by increasing the pacing frequency until stable alternans was observed (1.6–2.5 Hz at room temperature). In atrial myocytes, action potential-induced Ca release is initiated in the cell periphery and subsequently propagates towards the cell center by Ca-induced Ca release (CICR) in a Ca wave-like fashion, driven by the newly identified ‘fire-diffuse-uptake-fire’ (FDUF) mechanism. The development of CaT alternans was accompanied by characteristic changes of the spatio-temporal organization of the CaT. During the later phase of the CaT, central [Ca]i exceeded peripheral [Ca]i that was indicative of a reversal of the subcellular [Ca]i gradient from centripetal to centrifugal. This gradient reversal resulted in a reversal of CICR propagation, causing a secondary Ca release during the large-amplitude alternans CaT, thereby prolonging the CaT, enhancing Ca-release refractoriness and reducing Ca release on the subsequent beat, thus enhancing the degree of CaT alternans. Here, we propose the ‘reverse FDUF’ mechanism as a novel cellular mechanism of atrial CaT alternans, which explains how the uncoupling of central from peripheral Ca release leads to the reversal of propagating CICR and to alternans. Full article
(This article belongs to the Special Issue Calcium Regulation in the Cardiac Cells)
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