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(Circulation Research. 2009;105:737.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Cardiac Na⁺ Current Regulation by Pyridine Nucleotides

Man Liu, Shamarendra Sanyal, Ge Gao, Iman S. Gurung, Xiaodong Zhu, Georgia Gaconnet, Laurie J. Kerchner, Lijuan L. Shang, Christopher L.-H. Huang, Andrew Grace, Barry London, Samuel C. Dudley, Jr

From the Division in Cardiology (M.L., G. Gao, G. Gaconnet, L.L.S., S.C.D.), University of Illinois at Chicago and the Jesse Brown Veteran Affairs Medical Center, Ill; Department of Medicine (S.S.), Pulmonary Division, Duke University, Durham, NC; Department of Biochemistry (I.S.G., C.L.-H.H., A.G.), University of Cambridge, United Kingdom; and the Cardiovascular Institute (X.Z., L.J.K., B.L.), University of Pittsburgh, Pa.

Correspondence to Dr. Samuel C. Dudley, Jr, Section of Cardiology, University of Illinois at Chicago/Jesse Brown VA Medical Center, 840 S Wood St, MC715, Chicago, IL 60612. E-mail scdudley{at}uic.edu

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_v1.5).

Methods and Results: HEK293 cells stably expressing Na_v1.5 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_v1.5 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_v1.5 by altering the oxidized to reduced NAD(H) balance.

Key Words: arrhythmias • electrophysiology • ion channels • sudden death

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				M. Chahine Cardiac Metabolic State and Brugada Syndrome: A Link Revealed Circ. Res., October 9, 2009; 105(8): 721 - 723. [Full Text] [PDF]