TY - JOUR
T1 - Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels
AU - Fukuda, Koji
AU - Davies, Sean S.
AU - Nakajima, Tadashi
AU - Ong, Boon Hooi
AU - Kupershmidt, Sabina
AU - Fessel, Joshua
AU - Amarnath, Venkataraman
AU - Anderson, Mark E.
AU - Boyden, Penelope A.
AU - Viswanathan, Prakash C.
AU - Roberts, L. Jackson
AU - Balser, Jeffrey R.
PY - 2005/12
Y1 - 2005/12
N2 - 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, E 2-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.
AB - 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, E 2-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.
KW - Isoketals
KW - Lipid-peroxidation
KW - Myocardial infarction
KW - Sodium channels
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U2 - 10.1161/01.RES.0000195844.31466.e9
DO - 10.1161/01.RES.0000195844.31466.e9
M3 - Article
C2 - 16284182
AN - SCOPUS:33644665708
SN - 0009-7330
VL - 97
SP - 1262
EP - 1269
JO - Circulation research
JF - Circulation research
IS - 12
ER -