Abstract
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.
Highlights
Trical and structural remodeling of the atria
Oxidant generation and redox changes are important elements in the -adrenergic regulation of influx via the L-type calcium channel (ICa) [14], and altered calcium channel phosphorylation has been shown to contribute to the decrement in calcium channel activity during Atrial fibrillation (AF) [15]
To test the hypothesis that redox modulation contributes to the loss of ICa in human AF, we evaluated the impact of incubating myocytes isolated from AF patients with NAC
Summary
Trical and structural remodeling of the atria. Calcium influx via ICa triggers calcium release from intracellular stores and is an essential first step in excitation-contraction coupling and a critical determinant of atrial contractility. In addition to ICa [11], the ryanodine receptor, RyR2, and the transient outward Kϩ current, Ito, are redox-sensitive [12, 13] Each of these currents modulates the atrial action potential and atrial contractility. Oxidant generation and redox changes are important elements in the -adrenergic regulation of ICa [14], and altered calcium channel phosphorylation has been shown to contribute to the decrement in calcium channel activity during AF [15]. Intracellular redox state can modulate protein function by several additional pathways. Since glutathione can act as an intracellular NO acceptor, alterations in the level of total cellular glutathione may have important consequences for both the redox-dependent and the NO-dependent regulation of ion channel activity
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