Selective γ-ketoaldehyde scavengers protect NaV1.5 from oxidant-induced inactivation

T. Nakajima, S. S. Davies, E. Matafonova, F. Potet, V. Amarnath, K. A. Tallman, R. A. Serwa, N. A. Porter, J. R. Balser, S. Kupershmidt*, L. J. Roberts

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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 languageEnglish (US)
Pages (from-to)352-359
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume48
Issue number2
DOIs
StatePublished - Feb 2010

Keywords

  • Arrhythmia
  • Ion channels
  • Oxidative stress
  • Reactive carbonyls

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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