Abstract
Abstract P3034: Acute Reduction Of Cardiac Sodium Channel Nav1.5 Increases Mitochondrial Calcium And Rewires Cardiac Metabolism
Circulation research, Vol.131(S_1), p.AP3034
08/05/2022
DOI: 10.1161/res.131.suppl_1.P3034
Abstract
Byline: xiaoming zhang, THE UNIVERSITY OF IOWA, Iowa City, IA; Jared McLendon, Univ of Iowa, Iowa City, IA; Ethan J Anderson, UIowa- College of Pharmacy, Iowa City, IA; Barry London, UNIVERSITY OF IOWA, Iowa City, IA; Ryan L Boudreau, UNIVERSITY OF IOWA, Iowa City, IA SCN5A encodes the voltage-gated Na+ channel Nav1.5, 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 Nav1.5 in mouse hearts (by AAV:Cre in SCN5A-flox mice) elicits metabolic changes. Both SCN5A+/fl and SCN5Afl/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+/Ca2+ imbalance. We found that acute reduction of myocardial Nav1.5 expression in mice leads to reduced mitochondrial Na+/Ca2+ exchanger (Nclx) protein levels, supporting potential crosstalk between these proteins, which is consistent with recent data suggesting that inward Na+ via Nav1.5 primes Nclx to promote Ca2+ efflux from nearby mitochondria. Indeed, we found that acute silencing of Nav1.5 expression leads to increased mitochondrial Ca2+ in cardiomyocytes. Overall, these data further highlight an important Nav1.5 interface with mitochondrial biology and support the notion that reduced Nav1.5 levels triggers ROS accumulation and metabolic imbalances in heart, which may exacerbate HF in patients.
Details
- Title: Subtitle
- Abstract P3034: Acute Reduction Of Cardiac Sodium Channel Nav1.5 Increases Mitochondrial Calcium And Rewires Cardiac Metabolism
- Creators
- xiaoming zhangJared McLendonEthan J AndersonBarry LondonRyan L Boudreau
- Resource Type
- Abstract
- Publication Details
- Circulation research, Vol.131(S_1), p.AP3034
- Publisher
- Lippincott Williams & Wilkins, WK Health
- DOI
- 10.1161/res.131.suppl_1.P3034
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 08/05/2022
- Description audience
- Academic
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Cardiovascular Medicine; Health and Human Physiology
- Record Identifier
- 9984339358602771
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