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An age-associated reduction in Nav1.5 protein expression correlates with an increase in Nav1.8 protein expression in the right atrial appendage of the human heart.

Isaac, Emmanuel; Cooper, Stephanie; Lancaster, Matthew; Loubani, Mahmoud; Jones, Sandra

Authors

Emmanuel Isaac

Stephanie Cooper

Matthew Lancaster

Mahmoud Loubani



Abstract

Background: Nav1.5 is the predominantly expressed voltage-gated sodium channel (VGSC) isoform in the heart, responsible for phase 0 of the action potential. Our rodent studies have shown expression of neuronal isoform Nav1.8 protein in the adult heart. Others have associated Nav1.8 expression with aberrant sodium currents leading to increased frequency of arrhythmogenic episodes.
Aim: To investigate age-associated changes in the protein expression of VGSCs Nav1.5 and Nav1.8 in the right atrial appendage of the human heart.
Methods: Tissues from the right atrial appendage were obtained from patients undergoing routine cardiac surgery, coronary artery bypass or valve repair. The protein expression of VGSC isoforms Nav1.5 and Nav1.8 were quantified using specific protein-directed primary antibodies (Alomone, Israel) coupled with a secondary antibody conjugated to HRP for western blot (Abcam, UK), or Alexa Fluor 488 (ThermoFisher, UK) for immunohistochemistry with confocal microscopy (LSM 710 Zeiss, UK). Densities were quantified using Image J software.
Results: Derived from 26 patients, the protein expression of Nav1.5 arranged in chronological age order (43-87 years of age) demonstrated a negative correlation between increasing age and Nav1.5 protein expression (Pearson correlation coefficient of -0.25). The contrary was shown for Nav1.8, which had a positive correlation with increasing age (Pearson correlation coefficient of 0.26), as older patients show increased Nav1.8 protein expression. This novel finding was reflected when we compared confocal images from elderly patients with their younger counterparts, as the elderly showed a higher density of labelled Nav1.8 protein and a lower density of labelled Nav1.5 protein, particularly located at the t-tubules and intercalated disks.
Conclusion: With increasing chronological age, the human heart reduces expression of the predominant cardiac isoform Nav1.5 whilst increasing the expression of Nav1.8: This finding has the potential to increase the risk of an elderly person’s heart to the susceptibility of arrhythmias.

Citation

Isaac, E., Cooper, S., Lancaster, M., Loubani, M., & Jones, S. (2020). An age-associated reduction in Nav1.5 protein expression correlates with an increase in Nav1.8 protein expression in the right atrial appendage of the human heart. Circulation Research, 127(Suppl_1), A493

Presentation Conference Type Conference Abstract
Conference Name Basic Cardiovascular Sciences Scientific Sessions 2020
Acceptance Date Jul 1, 2020
Online Publication Date Oct 27, 2020
Publication Date Oct 27, 2020
Deposit Date Nov 6, 2020
Journal Circulation Research
Print ISSN 1524-4571
Publisher American Heart Association
Peer Reviewed Peer Reviewed
Volume 127
Issue Suppl_1
Article Number 493
Pages A493
Keywords Ion channels, Sodium channel, atrial arrhythmia
Public URL https://hull-repository.worktribe.com/output/3654392
Publisher URL https://www.ahajournals.org/doi/abs/10.1161/res.127.suppl_1.493