Abstract
Abstract 5346: Regulation of Cardiac Na + Current by Pyridine Nucleotides: A Possible Explanation of Glycerol-3-Phosphate Dehydrogenase-Linked Brugada Syndrome
Circulation (New York, N.Y.), Vol.118(suppl_18)
10/28/2008
DOI: 10.1161/circ.118.suppl_18.S_532-b
Abstract
Recently, glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) gene mutations have been shown to reduce cardiac Na
+
current and cause Brugada Syndrome (BrS). The glycerol-3-phosphate dehydrogenase (GPD) family of genes is involved in nicotinamide adenine dinucleotides (NAD)-dependent energy metabolism, and GDP1-L has >80% amino acid homology with GPD. Therefore, we tested whether mutations in GPD1-L could be acting through NAD (H) to alter Na
+
current. Human embryonic kidney (HEK) cells stably expressing the human cardiac sodium channel (SCN5A) were used to assess the effects of wild-type (WT) and mutant (MT) GPD1-L on cellular NAD(H) and the effects of NAD(H) on Na
+
current. A mouse model of BrS was used to assess the effect of reduced NAD
+
on arrhythmic risk. MT GPD1-L raised cellular NADH level by 4.3 fold (p<0.01) and reduced Na
+
current by 69.9% (p<0.01). Extracellular NADH (300 μM) raised cellular NADH by 5.3 fold and decreased whole cell peak conductance by 71.4% (p<0.001). Extracellular NAD
+
(300 μM) raised conductance by 30.3% (p< 0.001). Fluorescent microscopy showed parallel changes in membrane-associated, GFP-tagged Na
+
channels. Intracellular application of NADH or NAD
+
resulted in an immediate change in Na
+
current of −55.5% (p < 0.01) and +66.6% (p < 0.01), respectively. External NAD
+
could prevent the reduction in Na
+
current caused by MT GPD1-L. Apocynin (100 μM), an NAD(P)H oxidase inhibitor, or the reducing agent, dithiothreitol (DTT), prevented the NADH-induced reduction in Na
+
current (p < 0.01). Application of 100 μM NAD
+
to a mouse model of BrS reduced the programmed electrical stimulation induced ventricular tachycardia. GPD1-L mutations may cause BrS through alterations in cellular NAD(H), and NAD
+
might represent a novel treatment for BrS.
Details
- Title: Subtitle
- Abstract 5346: Regulation of Cardiac Na + Current by Pyridine Nucleotides: A Possible Explanation of Glycerol-3-Phosphate Dehydrogenase-Linked Brugada Syndrome
- Creators
- Shamarendra Sanyal - Duke UniversityIman S Gurung - University of CambridgeArnold E Pfahnl - University of Illinois at ChicagoLijuan L Shang - University of Illinois at ChicagoShahriar Iravanian - University of Illinois at ChicagoJon Allen - University of Illinois at ChicagoMan Liu - University of Illinois at ChicagoAndrew Grace - University of CambridgeBarry London - University of PittsburghSamuel C Dudley - University of Illinois at Chicago
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.118(suppl_18)
- DOI
- 10.1161/circ.118.suppl_18.S_532-b
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 10/28/2008
- Academic Unit
- Internal Medicine; Molecular Physiology and Biophysics; Cardiovascular Medicine
- Record Identifier
- 9984302195302771
Metrics
1 Record Views