Atrial glutathione content, calcium current, and contractility

Cynthia A. Carnes, Paul M.L. Janssen, Mary L. Ruehr, Hitomi Nakayama, Tomohiro Nakayama, Hannelore Haase, John Anthony Bauer, Mina K. Chung, Ian M. Fearon, A. Marc Gillinov, Robert L. Hamlin, David R. Van Wagoner

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

Atrial fibrillation (AF) is characterized by decreased L-type calciumcurrent (ICa,L) in atrial myocytes and decreased atrial contractility. Oxidant stress and redox modulation of calcium channels are implicated in these pathologic changes. We evaluated the relationship between glutathione content (the primary cellular reducing moiety) and ICa,L in atrial specimens from AF patients undergoing cardiac surgery. Left atrial glutathione content was significantly lower in patients with either paroxysmal or persistent AF relative to control patients with no history of AF. Incubation of atrial myocytes from AF patients (but not controls) with the glutathione precursor N-acetylcysteine caused a marked increase in ICa,L. To test the hypothesis that glutathione levels were mechanistically linked with the reduction in ICa,L, dogs were treated for 48 h with buthionine sulfoximine, an inhibitor of glutathione synthesis. Buthionine sulfoximine treatment resulted in a 24% reduction in canine atrial glutathione content, a reduction in atrial contractility, and an attenuation of ICa,L in the canine atrial myocytes. Incubation of these myocytes with exogenous glutathione also restored ICa,L to normal or greater than normal levels. To probe the mechanism linking decreased glutathione levels to down-regulation of ICa, the biotin switch technique was used to evaluate S-nitrosylation of calcium channels. S-Nitrosylation was apparent in left atrial tissues from AF patients; the extent of S-nitrosylation was inversely related to tissue glutathione content. S-Nitrosylation was also detectable in HEKcells expressing recombinant human cardiac calcium channel subunits following exposure to nitrosoglutathione. S-Nitrosylation may contribute to the glutathione-sensitive attenuation of ICa,L observed in AF.

Original languageEnglish
Pages (from-to)28063-28073
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number38
DOIs
StatePublished - Sep 21 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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