Transcriptional profiles of genes related to electrophysiological function in scn5a+/− murine hearts

Abstract

Abstract Background 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. Purpose This study examines relationships between its Scn5a+/− genotype, resulting transcriptional changes and the consequent phenotypic presentations of BrS. Methods Atrial and ventricular tissue samples were obtained from aged (11±3 months) wild-type (WT) and homozygous Scn5a+/− mice. Quantitative PCR was used to examine transcription of 60 genes underlying cardiac tissue excitability. Results Of selected protein-coding genes related to cardiomyocyte electrophysiological or homeostatic function, concentrations of mRNA transcribed from 15 differed significantly from WT. Despite halved 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 significant differences shown by the atria and ventricles were up- and downregulations, respectively. Conclusion 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. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Surrey; Medical Research Council