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Transcriptional profiles of genes related to electrophysiological function in Scn5a +/− murine hearts

Published version
Peer-reviewed

Change log

Authors

Takla, Michael 
Edling, Charlotte E. 
Zhang, Kevin 
Saadeh, Khalil 
Tse, Gary 

Abstract

Abstract: The Scn5a gene encodes the major pore‐forming Nav1.5 (α) subunit, of the voltage‐gated Na+ channel in cardiomyocytes. The key role of Nav1.5 in action potential initiation and propagation in both atria and ventricles predisposes organisms lacking Scn5a or carrying Scn5a mutations to cardiac arrhythmogenesis. Loss‐of‐function Nav1.5 genetic abnormalities account for many cases of the human arrhythmic disorder Brugada syndrome (BrS) and related conduction disorders. A murine model with a heterozygous Scn5a deletion recapitulates many electrophysiological phenotypes of BrS. This study examines the relationships between its Scn5a+/− genotype, resulting transcriptional changes, and the consequent phenotypic presentations of BrS. Of 62 selected protein‐coding genes related to cardiomyocyte electrophysiological or homeostatic function, concentrations of mRNA transcribed from 15 differed significantly from wild type (WT). Despite halving apparent ventricular Scn5a transcription heterozygous deletion did not significantly downregulate its atrial expression, raising possibilities of atria‐specific feedback mechanisms. Most of the remaining 14 genes whose expression differed significantly between WT and Scn5a+/− animals involved Ca2+ homeostasis specifically in atrial tissue, with no overlap with any ventricular changes. All statistically significant changes in expression were upregulations in the atria and downregulations in the ventricles. This investigation demonstrates the value of future experiments exploring for and clarifying links between transcriptional control of Scn5a and of genes whose protein products coordinate Ca2+ regulation and examining their possible roles in BrS.

Description

Funder: University of Surrey; Id: http://dx.doi.org/10.13039/501100003513

Keywords

ORIGINAL ARTICLE, ORIGINAL ARTICLES, arrhythmia, Brugada syndrome, mechanisms, sodium channel, transcription

Journal Title

Physiological Reports

Conference Name

Journal ISSN

2051-817X

Volume Title

9

Publisher

Sponsorship
Medical Research Council (MR/M001288/1)