Abstract
The cardiac sodium channel (SCN5A, NaV1.5) 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 NaV1.5 function in whole hearts can be modeled in cultured myocytes, where oxidants shift the availability curve of INa 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 γ-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 NaV1.5 and that the selective isoketal scavengers block voltage-dependent changes in sodium current by the oxidant tert-butylhydroperoxide, both in cells heterologously expressing NaV1.5 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.
Original language | English (US) |
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Pages (from-to) | 352-359 |
Number of pages | 8 |
Journal | Journal of Molecular and Cellular Cardiology |
Volume | 48 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2010 |
Funding
This study was supported with funds from National Institute of Health grants HL079365 and GM042056 (to L.J.R.) ES013125 to N.A.P. and GM56307 (to J.R.B.). We thank Dr. Svetlana Stepanovic for expert technical assistance. The stably expressing Na V 1.5–GFP cell line was a kind gift from Dr. Kathy Murray, VUMC.
Keywords
- Arrhythmia
- Ion channels
- Oxidative stress
- Reactive carbonyls
ASJC Scopus subject areas
- Molecular Biology
- Cardiology and Cardiovascular Medicine