Abstract P3034: Acute Reduction Of Cardiac Sodium Channel Nav1.5 Increases Mitochondrial Calcium And Rewires Cardiac Metabolism

Abstract

SCN5A encodes the voltage-gated Na + channel Na v 1.5, known for its role in cardiac conduction. However, we recently found unexpected links between lower SCN5A expression and increased non-arrhythmic death in heart failure (HF) patients. To test if lower SCN5A expression in mice causes worse HF, we subjected young heterozygous SCN5A null ( SCN5A +/- ) mice to transverse aortic constriction (TAC), a model of cardiac hypertrophy progressing to HF. Surprisingly, SCN5A +/- hearts resisted TAC-induced hypertrophy and showed gene expression changes consistent with metabolic inflexibility [i.e. maintained fatty acid oxidation (FAO), blunted shift to glycolysis]. Given published roles for Na + in mitochondrial redox biology and metabolism, we assessed related phenotypes in SCN5A +/- mice. We found that aged SCN5A +/- mouse hearts show increased reactive oxygen species (ROS) and transcriptomic changes indicative of elevated FAO and lower glycolysis. Metabolomics data revealed perturbed glycolytic flux in SCN5A +/- mouse hearts, and cardiomyofiber respiration assays showed that these hearts maintain elevated FAO after insulin. We assessed if acute reduction of Na v 1.5 in mouse hearts (by AAV:Cre in SCN5A -flox mice) elicits metabolic changes. Both SCN5A +/fl and SCN5A fl/fl mouse hearts at 3 weeks post-AAV:Cre injection (vs. AAV:GFP) showed robust dampening of mitochondrial gene expression and altered metabolite profiles, including decreases in several fatty acids. We explored the possibility that these observations may relate to mitochondrial Na + /Ca 2+ imbalance. We found that acute reduction of myocardial Na v 1.5 expression in mice leads to reduced mitochondrial Na + /Ca 2+ exchanger (Nclx) protein levels, supporting potential crosstalk between these proteins, which is consistent with recent data suggesting that inward Na + via Na v 1.5 primes Nclx to promote Ca 2+ efflux from nearby mitochondria. Indeed, we found that acute silencing of Na v 1.5 expression leads to increased mitochondrial Ca 2+ in cardiomyocytes. Overall, these data further highlight an important Na v 1.5 interface with mitochondrial biology and support the notion that reduced Na v 1.5 levels triggers ROS accumulation and metabolic imbalances in heart, which may exacerbate HF in patients.