Journal article
Cardiac Na+ Current Regulation by Pyridine Nucleotides
Circulation research, Vol.105(8), pp.737-745
10/09/2009
DOI: 10.1161/CIRCRESAHA.109.197277
PMCID: PMC2773656
PMID: 19745168
Abstract
Rationale: Mutations in glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) protein reduce cardiac Na+ current (I(Na)) and cause Brugada Syndrome (BrS). GPD1-L has >80% amino acid homology with glycerol-3-phosphate dehydrogenase, which is involved in NAD-dependent energy metabolism.
Objective: Therefore, we tested whether NAD(H) could regulate human cardiac sodium channels (Na(v)1.5).
Methods and results: HEK293 cells stably expressing Na(v)1.5 and rat neonatal cardiomyocytes were used. The influence of NADH/NAD+ on arrhythmic risk was evaluated in wild-type or SCN5A(+/-) mouse heart. A280V GPD1-L caused a 2.48+/-0.17-fold increase in intracellular NADH level (P<0.001). NADH application or cotransfection with A280V GPD1-L resulted in decreased I(Na) (0.48+/-0.09 or 0.19+/-0.04 of control group, respectively; P<0.01), which was reversed by NAD+, chelerythrine, or superoxide dismutase. NAD+ antagonism of the Na+ channel downregulation by A280V GPD1-L or NADH was prevented by a protein kinase (PK)A inhibitor, PKAI(6-22). The effects of NADH and NAD+ were mimicked by a phorbol ester and forskolin, respectively. Increasing intracellular NADH was associated with an increased risk of ventricular tachycardia in wild-type mouse hearts. Extracellular application of NAD+ to SCN5A(+/-) mouse hearts ameliorated the risk of ventricular tachycardia.
Conclusions: Our results show that Na(v)1.5 is regulated by pyridine nucleotides, suggesting a link between metabolism and I(Na). This effect required protein kinase C activation and was mediated by oxidative stress. NAD+ could prevent this effect by activating PKA. Mutations of GPD1-L may downregulate Na(v)1.5 by altering the oxidized to reduced NAD(H) balance.
Details
- Title: Subtitle
- Cardiac Na+ Current Regulation by Pyridine Nucleotides
- Creators
- Man Liu - Division in Cardiology, University of Illinois at Chicago and the Jesse Brown VAMC, Chicago, IL, USAShamarendra Sanyal - Department of Medicine, Pulmonary Division, Duke UniversityGe Gao - Division in Cardiology, University of Illinois at Chicago and the Jesse Brown VAMC, Chicago, IL, USAIman S Gurung - Department of Biochemistry, University of Cambridge, UKXiaodong Zhu - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA, USAGeorgia Gaconnet - Division in Cardiology, University of Illinois at Chicago and the Jesse Brown VAMC, Chicago, IL, USALaurie J Kerchner - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA, USALijuan L Shang - Division in Cardiology, University of Illinois at Chicago and the Jesse Brown VAMC, Chicago, IL, USAChristopher L-H Huang - Department of Biochemistry, University of Cambridge, UKAndrew Grace - Department of Biochemistry, University of Cambridge, UKBarry London - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA, USASamuel C Dudley - Division in Cardiology, University of Illinois at Chicago and the Jesse Brown VAMC, Chicago, IL, USA
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.105(8), pp.737-745
- DOI
- 10.1161/CIRCRESAHA.109.197277
- PMID
- 19745168
- PMCID
- PMC2773656
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 10/09/2009
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984025429702771
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