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J. Biol. Chem., Vol. 282, Issue 38, 28063-28073, September 21, 2007

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Atrial Glutathione Content, Calcium Current, and Contractility^*

From the ^aCollege of Pharmacy, ^bDavis Heart and Lung Research Institute, ^cDepartment of Physiology and Cell Biology, and ^eCollege of Veterinary Medicine, Ohio State University, Columbus, Ohio 43210, the Departments of ^dMolecular Cardiology, ^hCardiovascular Medicine, and ^jCardiothoracic Surgery, Cleveland Clinic, Cleveland, Ohio 44195, the ^fMax-Delbrück-Center for Molecular Medicine, Berlin, Germany, the ^gCenter for Cardiovascular Medicine, Columbus Children's Research Institute, Columbus, Ohio 43205, and the ⁱFaculty of Life Sciences, University of Manchester, Manchester M13 9PL, United Kingdom

Atrial fibrillation (AF) is characterized by decreased L-type calcium current (I_Ca,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 I_Ca,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 I_Ca,L. To test the hypothesis that glutathione levels were mechanistically linked with the reduction in I_Ca,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 I_Ca,L in the canine atrial myocytes. Incubation of these myocytes with exogenous glutathione also restored I_Ca,L to normal or greater than normal levels. To probe the mechanism linking decreased glutathione levels to down-regulation of I_Ca, 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 HEK cells expressing recombinant human cardiac calcium channel subunits following exposure to nitrosoglutathione. S-Nitrosylation may contribute to the glutathione-sensitive attenuation of I_Ca,L observed in AF.

Received for publication, June 13, 2007

^* This study was supported by National Institutes of Health Grants RO1 HL-65412 and RO1 HL-73816, American Heart Association Grants 0130309N and 0235045N, and a grant from the Atrial Fibrillation Innovation Center, an Ohio Wright Center Initiative. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Cardiology, M/S NE-61, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-0820; Fax: 216-444-9155; E-mail: vanwagd{at}ccf.org.

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