Atrial glutathione content, calcium current, and contractility
Atrial glutathione content, calcium current, and contractility
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DOI：
10.1074/jbc.m704893200
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发表时间：
2007-09-21
影响因子：
4.8
通讯作者：
Van Wagoner, David R.
中科院分区：
文献类型：
--
作者：
Carnes, Cynthia A.;Janssen, Paul M. L.;Van Wagoner, David R.
心房颤动（AF）的特征是心房肌细胞L型钙电流（I-Ca，I-L）降低和心房收缩力下降。氧化应激和钙通道的氧化还原调节与这些病理变化有关。我们评估了接受心脏手术的AF患者心房样本中谷胱甘肽含量（主要细胞还原部分）与I-Ca，I-L之间的关系。左心房谷胱甘肽含量显着降低，无论是阵发性或持续性AF患者相对于对照组患者没有AF的历史。从AF患者（但不是对照组）的心房肌细胞与谷胱甘肽前体N-乙酰半胱氨酸孵育引起I-Ca，I-L显着增加。为了检验谷胱甘肽水平与I-Ca，I-L减少机械相关的假设，用谷胱甘肽合成的抑制剂丁噻呋亚砜亚胺处理狗48小时。丁硫恩汀亚砜亚胺处理导致犬心房谷胱甘肽含量降低24%，心房收缩力降低，犬心房肌细胞中I-Ca、I-L衰减。孵育这些心肌细胞与外源性谷胱甘肽也恢复I-Ca，I-L正常或高于正常水平。为了探讨谷胱甘肽水平降低与I-Ca下调的机制，使用生物素开关技术来评估钙通道的S-亚硝基化。房颤患者左心房组织中S-亚硝基化明显; S-亚硝基化程度与组织谷胱甘肽含量呈负相关。在暴露于亚硝基谷胱甘肽后表达重组人心脏钙通道亚单位的HEK细胞中也可检测到S-亚硝基化。S-亚硝基化可能有助于AF中观察到的谷胱甘肽敏感的I-Ca、I-L衰减。
Atrial fibrillation (AF) is characterized by decreased L-type calcium current (I-Ca,I-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,I-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,I-L. To test the hypothesis that glutathione levels were mechanistically linked with the reduction in I-Ca,I-L, dogs were treated for 48 h with buthionine sulfoximine, an inhibitor of glutathione synthesis. Buthiontine sulfoximine treatment resulted in a 24% reduction in canine atrial glutathione content, a reduction in atrial contractility, and an attenuation Of I-Ca,I-L in the canine atrial myocytes. Incubation of these myocytes with exogenous glutathione also restored I-Ca,I-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,I-L observed in AF.