Intracellular Na+ Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis

Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca2+-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na+]i is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na+ homeostasis in SAN pacemaking and test whether [Na+]i dysregulation may contribute to SAN dysfunction. Methods: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na+ entry (Na+/Ca2+ exchanger, NCX) and removal (Na+/K+ ATPase, NKA). Results: We found that changes in intracellular Na+ homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX- and ankyrin-B-deficient mice due to altered feedback between the Ca2+ and membrane potential clocks underlying SAN firing. Conclusions: Our study generates new testable predictions and insight linking Na+ homeostasis to Ca2+ handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.

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In silico analysis of selenoprotein N (Gallus gallus): absence of EF-hand motif and the role of CUGS-helix domain in antioxidant protection

Metallomics ◽

10.1093/mtomcs/mfab004 ◽

2021 ◽

Vol 13 (3) ◽

Author(s):

Shi-Yong Zhu ◽

Li-Li Liu ◽

Yue-Qiang Huang ◽

Xiao-Wei Li ◽

Milton Talukder ◽

...

Keyword(s):

In Silico ◽

Common Ancestor ◽

In Silico Analysis ◽

Antioxidant Protection ◽

Jnk Pathway ◽

Downstream Target ◽

Ef Hand ◽

Silico Analysis

Abstract Selenoprotein N (SEPN1) is critical to the normal muscular physiology. Mutation of SEPN1 can raise congenital muscular disorder in human. It is also central to maturation and structure of skeletal muscle in chicken. However, human SEPN1 contained an EF-hand motif, which was not found in chicken. And the biochemical and molecular characterization of chicken SEPN1 remains unclear. Hence, protein domains, transcription factors, and interactions of Ca2+ in SEPN1 were analyzed in silico to provide the divergence and homology between chicken and human in this work. The results showed that vertebrates’ SEPN1 evolved from a common ancestor. Human and chicken's SEPN1 shared a conserved CUGS-helix domain with function in antioxidant protection. SEPN1 might be a downstream target of JNK pathway, and it could respond to multiple stresses. Human's SEPN1 might not combine with Ca2+ with a single EF-hand motif in calcium homeostasis, and chicken SEPN1 did not have the EF-hand motif in the prediction, indicating the EF-hand motif malfunctioned in chicken SEPN1.

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In-silico Analysis of the Role of Boundary Conditions in the Induced Drift of 2D Spiral Waves

2020 Ural Symposium on Biomedical Engineering, Radioelectronics and Information Technology (USBEREIT) ◽

10.1109/usbereit48449.2020.9117633 ◽

2020 ◽

Author(s):

Evgeniy Kuklin ◽

Sergei Pravdin

Keyword(s):

Boundary Conditions ◽

In Silico ◽

In Silico Analysis ◽

Spiral Waves ◽

Silico Analysis

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In-silico analysis and expression profiling implicate diverse role of EPSPS family genes in regulating developmental and metabolic processes

BMC Research Notes ◽

10.1186/1756-0500-7-58 ◽

2014 ◽

Vol 7 (1) ◽

pp. 58 ◽

Cited By ~ 10

Author(s):

Bharti Garg ◽

Neha Vaid ◽

Narendra Tuteja

Keyword(s):

Expression Profiling ◽

In Silico ◽

In Silico Analysis ◽

Metabolic Processes ◽

Silico Analysis

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Ribonucleotide Reductases from Bifidobacteria Contain Multiple Conserved Indels Distinguishing Them from All Other Organisms: In Silico Analysis of the Possible Role of a 43 aa Bifidobacteria-Specific Insert in the Class III RNR Homolog

Frontiers in Microbiology ◽

10.3389/fmicb.2017.01409 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 4

Author(s):

Seema Alnajar ◽

Bijendra Khadka ◽

Radhey S. Gupta

Keyword(s):

In Silico ◽

In Silico Analysis ◽

Class Iii ◽

Ribonucleotide Reductases ◽

Conserved Indels ◽

Silico Analysis

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Role of nitric oxide synthase in insect cell radioresistance: an in-silico analysis

Bioinformation ◽

10.6026/97320630003008 ◽

2008 ◽

Vol 3 (1) ◽

pp. 8-13 ◽

Cited By ~ 10

Author(s):

Shubhankar Suman ◽

Rakesh Kumar Seth ◽

Sudhir Chandna

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Insect Cell ◽

In Silico ◽

In Silico Analysis ◽

Oxide Synthase ◽

Silico Analysis

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Cardiac miRNAs were involved in the regulation of pathophysiological mechanisms underlying HF in pediatric patients after ventricular assist device implantation

European Heart Journal ◽

10.1093/eurheartj/ehab724.0941 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

R Ragusa ◽

A Di Molfetta ◽

S Del Turco ◽

G Basta ◽

M Rizzo ◽

...

Keyword(s):

Cardiac Muscle ◽

Real Time ◽

Mirna Expression ◽

Real Time Pcr ◽

In Silico ◽

In Silico Analysis ◽

Adiponectin Receptors ◽

Silico Analysis

Abstract Background VAD use in heart failure (HF) children have undergone rapid progress in the last three decades through pump technological innovation and improvement of perioperative care. Studies in HF adults showed that VAD put native heart at rest and lead to molecular changes in cardiac muscle, including at microRNA (miRNA) level. However, little is known on changes induced by VAD implant in cardiac miRNA expression and their putative targets in HF children. Purpose The aims of this study were to evaluate: 1) modification of miRNA expression in cardiac muscle from HF children after VAD support; 2) the putative targets of selected miRNAs by in silico analysis; 2) the role of the identify miRNAs on putative targets by in vitro study. Methods Cardiac biopsies were collected from HF children at the moment of VAD implant [n=8; 20 (7.5–64.5) months, 2 males; 19 (15.75–32.25) LVEF%] and at the time of heart transplant after VAD support [n=5; 32 (5–204) months; 4 males; 13.5 (10–18) LVEF%]. Cardiac miRNA expression was evaluated by NGS. The potential miRNA targets were identified by bioinformatics analyses and their cardiac expression by real-time PCR was evaluated. HL-1 cell line was used for testing the regulatory role of selected miRNA on predicted targets by miRNA mimic transfection study. Results At NGS, 465 miRNA were found on average in each sample and the cardiac expression levels of miR19a-3p, miR-1246 and miR-199b-5p decreased in HF children after VAD support compared to pre-implant (Fig. 1A-B). In silico analysis showed that more than 5000 potential gene targets regulated by miR-19a-3p, miR-1246 and miR-199b-5p. Among them, adiponectin receptors (AdipoR1, AdipoR2, T-CAD) were identified as common targets for 3 miRNAs. Real-time PCR data showed that levels of all adiponectin receptors increased significantly whilst the expression of 3 miRNAs decreased after VAD support (Fig. 1C). Moreover, AdipoR2 and T-CAD were inversely related to miRNA levels (Fig. 1D). In vitro studies confirmed the regulatory role of miR-1246 and miR-199b-5p on AdipoR2 (Fig. 1E-F), whilst only miR-199b-5p reduced the expression of T-CAD (Fig. 1G). Finally, AdipoR1 expression levels are not modified compared to control by miRNAs mimic transfection (data not shown). Conclusion In HF children the use of VAD could modify the expression of several miRNAs potentially involved in the regulation of several pathophysiological mechanisms underlying HF. Specifically, the reductions of miR-1246, mir-19a-3p, miR-199b-5p were associated with an increase of the adiponectin receptors AdipoR2 and T-CAD mRNA, suggesting the existence of a miRNAs related fine tuning of the adiponectin system at cardiac tissue level by VAD implant, able to favour the protective effect of adiponectin in HF cardiac muscle. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): FP7-ICT-2009 Project, Grant Agreement 24863 Figure 1

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