Selective gamma-ketoaldehyde scavengers protect Nav1.5 from oxidant-induced inactivation.
The cardiac sodium channel (SCN5A, Na(V)1.5) is a key determinant of electrical impulse conduction in cardiac tissue. Acute myocardial infarction leads to diminished sodium channel availability, both because of decreased channel expression and because of greater inactivation of channels already present. Myocardial infarction leads to significant increases in reactive oxygen species and their downstream effectors including lipoxidation products. The effects of reactive oxygen species on Na(V)1.5 function in whole hearts can be modeled in cultured myocytes, where oxidants shift the availability curve of I(Na) to hyperpolarized potentials, decreasing cardiac sodium current at the normal activation threshold. We recently examined potential mediators of the oxidant-induced inactivation and found that one specific lipoxidation product, the isoketals, recapitulated the effects of oxidant on sodium currents. Isoketals are highly reactive gamma-ketoaldehydes formed by the peroxidation of arachidonic acid that covalently modify the lysine residues of proteins. We now confirm that exposure to oxidants induces lipoxidative modification of Na(V)1.5 and that the selective isoketal scavengers block voltage-dependent changes in sodium current by the oxidant tert-butylhydroperoxide, both in cells heterologously expressing Na(V)1.5 and in a mouse cardiac myocyte cell line (HL-1). Thus, inhibition of this lipoxidative modification pathway is sufficient to protect the sodium channel from oxidant induced inactivation and suggests the potential use of isoketal scavengers as novel therapeutics to prevent arrhythmogenesis during myocardial infarction.
Nakajima
T
T
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232-0413, USA.
Davies
S S
SS
Matafonova
E
E
Potet
F
F
Amarnath
V
V
Tallman
K A
KA
Serwa
R A
RA
Porter
N A
NA
Balser
J R
JR
Kupershmidt
S
S
Roberts
L J
LJ
D000200:Action Potentials / Q000187:drug effects; D000447:Aldehydes / Q000378:metabolism*; D000588:Amines / Q000494:pharmacology; D002460:Cell Line; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000941:ethics*; D007700:Kinetics; D062554:NAV1.5 Voltage-Gated Sodium Channel; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D015222:Sodium Channels / Q000378:metabolism*; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D000447:Aldehydes; D000588:Amines; D016166:Free Radical Scavengers; D062554:NAV1.5 Voltage-Gated Sodium Channel; D016877:Oxidants; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D020122:tert-Butylhydroperoxide