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Biomedicines
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Regulation of Ca2+ Signals in Cardiovascular Biology
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Regulation of Ca2+ Signals in Cardiovascular Biology

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 6781

Special Issue Editor

Dr. Senka Ljubojevic-Holzer

E-Mail Website
Guest Editor
Department of Cardiology, Medical University of Graz, A-8036 Graz, Austria
Interests: calcium signaling; calcium transients; cardiac cells; vascular cells

Special Issue Information

Dear Colleagues,

Calcium (Ca2+) is a ubiquitous intracellular second messenger, and its regulation is a key component of numerous cellular functions of the cardiovascular system. Ca2+ controls excitation-contraction coupling in cardiomyocytes and influences signaling cascades involved in cell metabolism and survival, but also cellular remodeling and hypertrophy in different cellular entities of the heart. These diverse Ca2+-dependent processes occur simultaneously in a beating heart, but they are differently regulated in distinct cell types, especially under stress or upon a detrimental insult to the heart. Although disturbed Ca2+ homeostasis has been considered a hallmark of cardiac pathologies such as heart failure and cardiac arrhythmia, we are only beginning to understand how different Ca2+-mediated processes integrate to determine the overall structural and functional vulnerability of the heart.

In this Special Issue, we welcome studies and review articles focused on Ca2+ signaling in the cardiovascular system as pertaining to electrophysiology, excitation-contraction coupling, modulation of contractile function, mitochondrial function, energy supply-demand balance, immune response, cell death, and the regulation of gene transcription to address novel mechanistic insights and summarize the current state of research in cardiac (patho)physiology. Manuscripts with translational value will be particularly encouraged.

Dr. Senka Ljubojevic-Holzer
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. Biomedicines 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 2600 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 signaling
  • calcium transients
  • cardiomyocyte
  • cardiac cells
  • vascular cells
  • excitation-contraction coupling
  • cardiac electrophysiology
  • cardiac remodeling
  • vascular remodeling
  • hypertrophy
  • heart failure
  • arrhythmia
  • translational

Published Papers (4 papers)

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Research

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19 pages, 4209 KiB  
Article
The Junctophilin-2 Mutation p.(Thr161Lys) Is Associated with Hypertrophic Cardiomyopathy Using Patient-Specific iPS Cardiomyocytes and Demonstrates Prolonged Action Potential and Increased Arrhythmogenicity
by Joona Valtonen, Chandra Prajapati, Reeja Maria Cherian, Sari Vanninen, Marisa Ojala, Krista Leivo, Tiina Heliö, Juha Koskenvuo and Katriina Aalto-Setälä
Biomedicines 2023, 11(6), 1558; https://doi.org/10.3390/biomedicines11061558 - 27 May 2023
Cited by 1 | Viewed by 1925
Abstract
Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases; it is primarily caused by mutations in sarcomeric genes. However, HCM is also associated with mutations in non-sarcomeric proteins and a Finnish founder mutation for HCM in non-sarcomeric protein junctophilin-2 (JPH2) [...] Read more.
Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases; it is primarily caused by mutations in sarcomeric genes. However, HCM is also associated with mutations in non-sarcomeric proteins and a Finnish founder mutation for HCM in non-sarcomeric protein junctophilin-2 (JPH2) has been identified. This study aimed at assessing the issue of modelling the rare Finnish founder mutation in cardiomyocytes (CMs) differentiated from iPSCs; therefore, presenting the same cardiac abnormalities observed in the patients. To explore the abnormal functions in JPH2-HCM, skin fibroblasts from a Finnish patient with JPH2 p.(Thr161Lys) were reprogrammed into iPSCs and further differentiated into CMs. As a control line, an isogenic counterpart was generated using the CRISPR/Cas9 genome editing method. Finally, iPSC-CMs were evaluated for the morphological and functional characteristics associated with JPH2 mutation. JPH2-hiPSC-CMs displayed key HCM hallmarks (cellular hypertrophy, multi-nucleation, sarcomeric disarray). Moreover, JPH2-hiPSC-CMs exhibit a higher degree of arrhythmia and longer action potential duration associated with slower inactivation of calcium channels. Functional evaluation supported clinical observations, with differences in beating characteristics when compared with isogenic-hiPSC-CMs. Thus, the iPSC-derived, disease-specific cardiomyocytes could serve as a translationally relevant platform to study genetic cardiac diseases. Full article
(This article belongs to the Special Issue Regulation of Ca2+ Signals in Cardiovascular Biology)
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12 pages, 2264 KiB  
Article
Gq-Mediated Arrhythmogenic Signaling Promotes Atrial Fibrillation
by Felix Hohendanner, Ashok Prabhu, Nicola Wilck, Verena Stangl, Burkert Pieske, Karl Stangl and Till F. Althoff
Biomedicines 2023, 11(2), 526; https://doi.org/10.3390/biomedicines11020526 - 11 Feb 2023
Cited by 1 | Viewed by 1688
Abstract
Background: Atrial fibrillation (AF) is promoted by various stimuli like angiotensin II, endothelin-1, epinephrine/norepinephrine, vagal activation, or mechanical stress, all of which activate receptors coupled to G-proteins of the Gαq/Gα11-family (Gq). Besides pro-fibrotic and pro-inflammatory effects, G [...] Read more.
Background: Atrial fibrillation (AF) is promoted by various stimuli like angiotensin II, endothelin-1, epinephrine/norepinephrine, vagal activation, or mechanical stress, all of which activate receptors coupled to G-proteins of the Gαq/Gα11-family (Gq). Besides pro-fibrotic and pro-inflammatory effects, Gq-mediated signaling induces inositol trisphosphate receptor (IP3R)-mediated intracellular Ca2+ mobilization related to delayed after-depolarisations and AF. However, direct evidence of arrhythmogenic Gq-mediated signaling is absent. Methods and results: To define the role of Gq in AF, transgenic mice with tamoxifen-inducible, cardiomyocyte-specific Gαq/Gα11-deficiency (Gq-KO) were created and exposed to intracardiac electrophysiological studies. Baseline electrophysiological properties, including heart rate, sinus node recovery time, and atrial as well as AV nodal effective refractory periods, were comparable in Gq-KO and control mice. However, inducibility and mean duration of AF episodes were significantly reduced in Gq-KO mice—both before and after vagal stimulation. To explore underlying mechanisms, left atrial cardiomyocytes were isolated from Gq-KO and control mice and electrically stimulated to study Ca2+-mobilization during excitation–contraction coupling using confocal microscopy. Spontaneous arrhythmogenic Ca2+ waves and sarcoplasmic reticulum content-corrected Ca2+ sparks were less frequent in Gq-KO mice. Interestingly, nuclear but not cytosolic Ca2+ transient amplitudes were significantly decreased in Gq-KO mice. Conclusion: Gq-signaling promotes arrhythmogenic atrial Ca2+-release and AF in mice. Targeting this pathway, ideally using Gq-selective, biased receptor ligands, may be a promising approach for the treatment and prevention of AF. Importantly, the atrial-specific expression of the Gq-effector IP3R confers atrial selectivity mitigating the risk of life-threatening ventricular pro-arrhythmic effects. Full article
(This article belongs to the Special Issue Regulation of Ca2+ Signals in Cardiovascular Biology)
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Review

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14 pages, 1080 KiB  
Review
Dysregulated Calcium Handling in Cirrhotic Cardiomyopathy
by Sang Youn Hwang, Hongqun Liu and Samuel S. Lee
Biomedicines 2023, 11(7), 1895; https://doi.org/10.3390/biomedicines11071895 - 4 Jul 2023
Cited by 1 | Viewed by 809
Abstract
Cirrhotic cardiomyopathy is a syndrome of blunted cardiac systolic and diastolic function in patients with cirrhosis. However, the mechanisms remain incompletely known. Since contractility and relaxation depend on cardiomyocyte calcium transients, any factors that impact cardiac contractile and relaxation functions act eventually through [...] Read more.
Cirrhotic cardiomyopathy is a syndrome of blunted cardiac systolic and diastolic function in patients with cirrhosis. However, the mechanisms remain incompletely known. Since contractility and relaxation depend on cardiomyocyte calcium transients, any factors that impact cardiac contractile and relaxation functions act eventually through calcium transients. In addition, calcium transients play an important role in cardiac arrhythmias. The present review summarizes the calcium handling system and its role in cardiac function in cirrhotic cardiomyopathy and its mechanisms. The calcium handling system includes calcium channels on the sarcolemmal plasma membrane of cardiomyocytes, the intracellular calcium-regulatory apparatus, and pertinent proteins in the cytosol. L-type calcium channels, the main calcium channel in the plasma membrane of cardiomyocytes, are decreased in the cirrhotic heart, and the calcium current is decreased during the action potential both at baseline and under stimulation of beta-adrenergic receptors, which reduces the signal to calcium-induced calcium release. The study of sarcomere length fluctuations and calcium transients demonstrated that calcium leakage exists in cirrhotic cardiomyocytes, which decreases the amount of calcium storage in the sarcoplasmic reticulum (SR). The decreased storage of calcium in the SR underlies the reduced calcium released from the SR, which results in decreased cardiac contractility. Based on studies of heart failure with non-cirrhotic cardiomyopathy, it is believed that the calcium leakage is due to the destabilization of interdomain interactions (dispersion) of ryanodine receptors (RyRs). A similar dispersion of RyRs may also play an important role in reduced contractility. Multiple defects in calcium handling thus contribute to the pathogenesis of cirrhotic cardiomyopathy. Full article
(This article belongs to the Special Issue Regulation of Ca2+ Signals in Cardiovascular Biology)
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19 pages, 1890 KiB  
Review
Nuclear Calcium in Cardiac (Patho)Physiology: Small Compartment, Big Impact
by Mara Kiessling, Nataša Djalinac, Julia Voglhuber and Senka Ljubojevic-Holzer
Biomedicines 2023, 11(3), 960; https://doi.org/10.3390/biomedicines11030960 - 21 Mar 2023
Cited by 2 | Viewed by 1792
Abstract
The nucleus of a cardiomyocyte has been increasingly recognized as a morphologically distinct and partially independent calcium (Ca2+) signaling microdomain, with its own Ca2+-regulatory mechanisms and important effects on cardiac gene expression. In this review, we (1) provide a [...] Read more.
The nucleus of a cardiomyocyte has been increasingly recognized as a morphologically distinct and partially independent calcium (Ca2+) signaling microdomain, with its own Ca2+-regulatory mechanisms and important effects on cardiac gene expression. In this review, we (1) provide a comprehensive overview of the current state of research on the dynamics and regulation of nuclear Ca2+ signaling in cardiomyocytes, (2) address the role of nuclear Ca2+ in the development and progression of cardiac pathologies, such as heart failure and atrial fibrillation, and (3) discuss novel aspects of experimental methods to investigate nuclear Ca2+ handling and its downstream effects in the heart. Finally, we highlight current challenges and limitations and recommend future directions for addressing key open questions. Full article
(This article belongs to the Special Issue Regulation of Ca2+ Signals in Cardiovascular Biology)
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