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

Michael Takla,Christopher L-H Huang,Kevin Zhang,Khalil Saadeh,Gary Tse,Samantha C Salvage,Charlotte E Edling,Kamalan Jeevaratnam

doi:10.14814/phy2.15043

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.

Highlights

The Brugada syndrome (BrS) poses a major worldwide public health problem, accounting for one in five sudden cardiac deaths among patients without reported structural cardiac defects (Antzelevitch et al, 2005; Matsuo et al, 2001)
This study examines the effects of diminished expression of Nav1.5 on the transcriptome of murine atrial and ventricular cardiomyocytes, and, in turn, the extent to which such significant changes reflect or explain electrophysiological observations
It surveys transcriptional changes in Scn5a+/− murine hearts hitherto used as an experimental model for BrS and related clinical conditions

Summary

| INTRODUCTION

The Brugada syndrome (BrS) poses a major worldwide public health problem, accounting for one in five sudden cardiac deaths among patients without reported structural cardiac defects (Antzelevitch et al, 2005; Matsuo et al, 2001). The BrS phenotype has been associated with close to 300 distinct genomic mutations (Kapplinger et al, 2010) though in most their causal relationships with the arrhythmic phenotype are not directly apparent (Hosseini et al, 2018). This abundance and diversity of disease- causing variants suggests that that aging interacts with a polygenic, rather than Mendelian, background in producing BrS phenotypes. This study explores the possible contributions of transcriptional alterations involving genes potentially related to electrophysiological phenotypes following heterozygotic Scn5a deletion in a murine model

| MATERIALS AND METHODS

| RESULTS

| DISCUSSION