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Modulation of the cardiac sodium channel Na1.5 peak and late currents by NAD precursors. | LitMetric

Modulation of the cardiac sodium channel Na1.5 peak and late currents by NAD precursors.

J Mol Cell Cardiol

Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America; Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America. Electronic address:

Published: April 2020

AI Article Synopsis

  • - The sodium channel Na1.5, encoded by SCN5A, is essential for heart function, and its dysfunction can lead to serious heart rhythm issues and sudden cardiac death.
  • - The study aimed to explore how NAD precursors, specifically nicotinamide riboside (NR) and nicotinamide (NAM), influence Na1.5 activity and cardiac function, with findings showing NR increased Na1.5 current in specific cell types.
  • - Results indicated that while NR enhanced Na1.5 activity by altering acetylation and potentially phosphorylation, NAM did not affect Na1.5 current under certain conditions, suggesting different roles for these precursors in cardiac electrophysiology.

Article Abstract

Rationale: The cardiac sodium channel Na1.5, encoded by SCN5A, produces the rapidly inactivating depolarizing current I that is responsible for the initiation and propagation of the cardiac action potential. Acquired and inherited dysfunction of Na1.5 results in either decreased peak I or increased residual late I (I), leading to tachy/bradyarrhythmias and sudden cardiac death. Previous studies have shown that increased cellular NAD and NAD/NADH ratio increase I through suppression of mitochondrial reactive oxygen species and PKC-mediated Na1.5 phosphorylation. In addition, NAD-dependent deacetylation of Na1.5 at K1479 by Sirtuin 1 increases Na1.5 membrane trafficking and I. The role of NAD precursors in modulating I remains unknown.

Objective: To determine whether and by which mechanisms the NAD precursors nicotinamide riboside (NR) and nicotinamide (NAM) affect peak I and Iin vitro and cardiac electrophysiology in vivo.

Methods And Results: The effects of NAD precursors on the NAD metabolome and electrophysiology were studied using HEK293 cells expressing wild-type and mutant Na1.5, rat neonatal cardiomyocytes (RNCMs), and mice. NR increased I in HEK293 cells expressing Na1.5 (500 μM: 51 ± 18%, p = .02, 5 mM: 59 ± 22%, p = .03) and RNCMs (500 μM: 60 ± 26%, p = .02, 5 mM: 74 ± 39%, p = .03) while reducing I at the higher concentration (RNCMs, 5 mM: -45 ± 11%, p = .04). NR (5 mM) decreased Na1.5 K1479 acetylation but increased I in HEK293 cells expressing a mutant form of Na1.5 with disruption of the acetylation site (Na1.5-K1479A). Disruption of the PKC phosphorylation site abolished the effect of NR on I. Furthermore, NAM (5 mM) had no effect on I in RNCMs or in HEK293 cells expressing wild-type Na1.5, but increased I in HEK293 cells expressing Na1.5-K1479A. Dietary supplementation with NR for 10-12 weeks decreased QTc in C57BL/6 J mice (0.35% NR: -4.9 ± 2.0%, p = .14; 1.0% NR: -9.5 ± 2.8%, p = .01).

Conclusions: NAD precursors differentially regulate Na1.5 via multiple mechanisms. NR increases I, decreases I, and warrants further investigation as a potential therapy for arrhythmic disorders caused by Na1.5 deficiency and/or dysfunction.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234910PMC
http://dx.doi.org/10.1016/j.yjmcc.2020.01.013DOI Listing

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