Intracellular sodium elevation reprograms cardiac metabolism

Dunja Aksentijević, Anja Karlstaedt, Marina V. Basalay, Brett A. O’Brien, David Sanchez-Tatay, Seda Eminaga, Alpesh Thakker, Daniel A. Tennant, William Fuller, Thomas R. Eykyn, Heinrich Taegtmeyer and Michael J. Shattock ()
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Dunja Aksentijević: School of Cardiovascular and Medical Sciences, British Heart Foundation Centre of Research Excellence, King’s College London, The Rayne Institute, St Thomas’ Hospital
Anja Karlstaedt: Division of Cardiology, McGovern Medical School The University of Texas Health Science Center at Houston
Marina V. Basalay: School of Cardiovascular and Medical Sciences, British Heart Foundation Centre of Research Excellence, King’s College London, The Rayne Institute, St Thomas’ Hospital
Brett A. O’Brien: School of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital
David Sanchez-Tatay: School of Cardiovascular and Medical Sciences, British Heart Foundation Centre of Research Excellence, King’s College London, The Rayne Institute, St Thomas’ Hospital
Seda Eminaga: School of Cardiovascular and Medical Sciences, British Heart Foundation Centre of Research Excellence, King’s College London, The Rayne Institute, St Thomas’ Hospital
Alpesh Thakker: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences University of Birmingham
Daniel A. Tennant: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences University of Birmingham
William Fuller: Institute of Cardiovascular and Medical Sciences, University of Glasgow
Thomas R. Eykyn: School of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital
Heinrich Taegtmeyer: Division of Cardiology, McGovern Medical School The University of Texas Health Science Center at Houston
Michael J. Shattock: School of Cardiovascular and Medical Sciences, British Heart Foundation Centre of Research Excellence, King’s College London, The Rayne Institute, St Thomas’ Hospital

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Intracellular Na elevation in the heart is a hallmark of pathologies where both acute and chronic metabolic remodelling occurs. Here, we assess whether acute (75 μM ouabain 100 nM blebbistatin) or chronic myocardial Nai load (PLM3SA mouse) are causally linked to metabolic remodelling and whether the failing heart shares a common Na-mediated metabolic ‘fingerprint’. Control (PLMWT), transgenic (PLM3SA), ouabain-treated and hypertrophied Langendorff-perfused mouse hearts are studied by 23Na, 31P, 13C NMR followed by 1H-NMR metabolomic profiling. Elevated Nai leads to common adaptive metabolic alterations preceding energetic impairment: a switch from fatty acid to carbohydrate metabolism and changes in steady-state metabolite concentrations (glycolytic, anaplerotic, Krebs cycle intermediates). Inhibition of mitochondrial Na/Ca exchanger by CGP37157 ameliorates the metabolic changes. In silico modelling indicates altered metabolic fluxes (Krebs cycle, fatty acid, carbohydrate, amino acid metabolism). Prevention of Nai overload or inhibition of Na/Camito may be a new approach to ameliorate metabolic dysregulation in heart failure.

Date: 2020
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DOI: 10.1038/s41467-020-18160-x

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