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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Stimulation of NOX2 in isolated hearts reversibly sensitizes RyR2 channels to activation by cytoplasmic calcium
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Stimulation of NOX2 in isolated hearts reversibly sensitizes RyR2 channels to activation by cytoplasmic calcium

机译：在离体心脏中刺激NOX2可逆地使RyR2通道对细胞质钙的激活敏感

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摘要

The response of ryanodine receptor (RyR) channels to cytoplasmic free calcium concentration ([Ca ]) is redox sensitive. Here, we report the effects of a mild oxidative stress on cardiac RyR (RyR2) channels in Langendorff perfused rat hearts. Single RyR2 channels from control ventricles displayed the same three responses to Ca~(2+) reported in other mammalian tissues, characterized by low, moderate, or high maximal activation. A single episode of 5 min of global ischemia, followed by 1 min of reperfusion, enhanced 2.3-fold the activity of NOX2 compared to controls and changed the frequency distribution of the different responses of RyR2 channels to calcium, favoring the more active ones: high activity response increased and low activity response decreased with respect to controls. This change was fully prevented by perfusion with apocynin or VAS 2870 before ischemia and totally reversed by the extension of the reperfusion period to 15 min. In vitro activation of N0X2 in control SR vesicles mimicked the effect of the ischemia/reperfusion episode on the frequencies of emergence of single RyR2 channel responses to [Ca~(2+)] and increased 2.2-fold the rate of calcium release in Ca~(2+)-loaded SR vesicles. In vitro changes were reversed at the single channel level by DTT and in isolated SR vesicles by glutaredoxin. Our results indicate that in whole hearts a mild oxidative stress enhances the response of cardiac RyR2 channels to calcium via N0X2 activation, probably by S-glutathionylation of RyR2 protein. This change is transitory and fully reversible, suggesting a possible role of redox modification in the physiological response of cardiac RyR2 to cellular calcium influx.
机译：ryanodine受体（RyR）通道对细胞质游离钙浓度（[Ca]）的响应是氧化还原敏感的。在这里，我们报告在Langendorff灌注大鼠心脏中轻度氧化应激对心脏RyR（RyR2）通道的影响。对照心室中的单个RyR2通道对其他哺乳动物组织中报道的Ca〜（2+）表现出相同的三种反应，其特征是低，中或高的最大激活。全身缺血5分钟后再灌注1分钟，与对照组相比，NOX2的活性增强了2.3倍，并改变了RyR2通道对钙的不同反应的频率分布，偏爱活性更高的通道：相对于对照，活动反应增加而低活动反应减少。通过在缺血前灌注载脂蛋白或VAS 2870可以完全防止这种变化，并且通过将再灌注时间延长至15分钟可以完全逆转这种变化。对照SR囊泡中N0X2的体外活化模拟了缺血/再灌注事件对[Ca〜（2+）]的单个RyR2通道反应出现频率的影响，并使Ca〜的钙释放速率增加了2.2倍（2 +）加载SR囊泡。 DTT可在单通道水平逆转体外变化，而戊二醛毒素可分离离体SR囊泡。我们的结果表明，在整个心脏中，轻度的氧化应激可能会通过N0X2激活（可能是RyR2蛋白的S-谷胱甘肽酰化）增强心脏RyR2通道对钙的反应。这种变化是暂时的并且是完全可逆的，表明氧化还原修饰在心脏RyR2对细胞钙流入的生理反应中的可能作用。

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