The Cardiomyocyte Molecular Clock Regulates the Functional Expression of Scn5a

The importance of Scn5a (Nav1.5) for cardiac electrical stability is highlighted by the fact that genetic defects lead to lethal arrhythmias, and changes in the expression of Scn5a are implicated in arrhythmogenic risk with heart failure. Nav1.5 is responsible for conducting most of the Na+ current (INa) in the heart and, along with gap junctions, it is a major determinant of impulse conduction velocity in cardiac tissues. Loss of function Scn5a mutations decrease peak INa and result in a wide range of clinical phenotypes including Brugada syndrome (BrS), cardiac conduction diseases, and dilated cardiomyopathy. Gain of function Scn5a mutations that increase the small “late” INa during the action potential plateau phase cause long QT syndrome type 3 (LQT3) and increase the risk for torsades de pointes. Experimental and clinical evidence demonstrate that the transcriptional regulation of Scn5a is a candidate mechanism for influencing arrhythmia susceptibility. Single Nucleotide Polymorphisms (SNPs) in the core Scn5a promoter that decrease activity are linked to slower cardiac conduction, increased sensitivity to drugs that block INa (class I anti-arrhythmic drugs), and more severe cases of BrS. Moreover, a series of genome-wide association studies (GWAS) focused on the QRS interval (an index of cardiac conduction) have identified transcription factors that regulate Scn5a expression (e.g Tbx5). We recently published that Bmal1, which encodes a core circadian molecular clock transcription factor, underlies the circadian expression of Scn5a and loss of Bmal1 function in the heart causes ~50% reduction in Nav1.5 levels and a ~30% reduction in peak INa. These data are exciting because linking the transcriptional regulation of Scn5a to the molecular clock suggests that environmental cues, like the timing of the light cycle, directly contributes to Scn5a expression and arrhythmia susceptibility. The goal of this proposal is to identify gene-environment interactions that directly contribute to transcriptional and functional regulation of Scn5a expression. Successful completion of this proposal will identify candidate behaviors or life-styles that improve the management of patients with an Scn5a channelopathy.