Reduced Expression of the Cardiac Sodium Channel Nav1.5 Triggers Enhanced Fatty Acid Metabolism and Oxidative Stress

SCN5A encodes the voltage-gated Na+ channel Nav1.5 that is best known for its role in cardiac conduction. We recently identified a microRNA (miR-24) binding site within the SCN5A coding region and found that its activity is modulated by an adjacent synonymous SNP (rs1805126). In humans, we linked the rs1805126 minor allele with decreased cardiac SCN5A expression and increased non-arrhythmic death in HF patients. To understand how lower SCN5A expression may lead to worse HF, we evaluated SCN5A +/- haploinsufficient mice, which develop cardiac fibrosis after 12 months of age. Given that oxidative stress often precedes fibrosis and is increased in HF, we assessed ROS levels in SCN5A +/- mouse hearts and found a 2.5-fold increase relative to wildtype (WT) hearts. We also performed co-expression analyses using human cardiac mRNA profiling data and unexpectedly found that SCN5A is linked to PPARA , a key driver of fatty acid oxidation (FAO, a predominant source of cardiac ROS), and to gene networks related to glucose metabolism and oxidative phosphorylation (OXPHOS). Along these lines, we found that SCN5A +/- mouse hearts show mRNA changes indicative of increased FAO/OXPHOS and decreased glycolysis, with a coincident broad up-regulation of PPAR target genes. Metabolomics data further indicated that glycolytic flux is perturbed in SCN5A +/- mouse hearts, and cardiac myofiber respiration assays showed that these hearts exhibit enhanced FAO. To test if SCN5A +/- mice suffer worse HF outcomes, we subjected young adult male mice to thoracic aortic constriction (TAC), a model of cardiac hypertrophy progressing to HF. While WT mice showed typical hypertrophic responses and signs of HF, SCN5A +/- hearts were resistant to TAC-induced hypertrophy, which based on prior reports, may be the result of elevated FAO. Overall, our data support the notion that lower cardiac SCN5A expression leads to an overreliance on FAO and accumulation of ROS in heart, which may exacerbate HF in patients. Together, our studies point to unforeseen roles for Nav1.5 in cardiac metabolism, opening several new paths of investigation. Future studies will interrogate 1) if human hearts with low SCN5A expression show signs of oxidative stress, and 2) if SCN5A +/- mice suffer worse HF after myocardial infarction.