Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels.
Sudden cardiac death attributable to ventricular tachycardia/fibrillation (VF) remains a catastrophic outcome of myocardial ischemia and infarction. At the same time, conventional antagonist drugs targeting ion channels have yielded poor survival benefits. Although pharmacological and genetic models suggest an association between sodium (Na+) channel loss-of-function and sudden cardiac death, molecular mechanisms have not been identified that convincingly link ischemia to Na+ channel dysfunction and ventricular arrhythmias. Because ischemia can evoke the generation of reactive oxygen species, we explored the effect of oxidative stress on Na+ channel function. We show here that oxidative stress reduces Na+ channel availability. Both the general oxidant tert-butyl-hydroperoxide and a specific, highly reactive product of the isoprostane pathway of lipid peroxidation, E2-isoketal, potentiate inactivation of cardiac Na+ channels in human embryonic kidney (HEK)-293 cells and cultured atrial (HL-1) myocytes. Furthermore, E2-isoketals were generated in the epicardial border zone of the canine healing infarct, an arrhythmogenic focus where Na+ channels exhibit similar inactivation defects. In addition, we show synergistic functional effects of flecainide, a proarrhythmic Na+ channel blocker, and oxidative stress. These data suggest Na+ channel dysfunction evoked by lipid peroxidation is a candidate mechanism for ischemia-related conduction abnormalities and arrhythmias.
Fukuda
Koji
K
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Davies
Sean S
SS
Nakajima
Tadashi
T
Ong
Boon-Hooi
BH
Kupershmidt
Sabina
S
Fessel
Joshua
J
Amarnath
Venkataraman
V
Anderson
Mark E
ME
Boyden
Penelope A
PA
Viswanathan
Prakash C
PC
Roberts
L Jackson
LJ
Balser
Jeffrey R
JR
D000447:Aldehydes / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002460:Cell Line; D005424:Flecainide / Q000494:pharmacology; D006801:Humans; D028421:Isoprostanes / Q000378:metabolism; D015227:Lipid Peroxidation; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress; D015222:Sodium Channels / Q000502:physiology*; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D000447:Aldehydes; D028421:Isoprostanes; D015222:Sodium Channels; D020122:tert-Butylhydroperoxide; D005424:Flecainide