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首页> 外文期刊>International Journal of Physiology, Pathophysiology and Pharmacology >NOS1AP modulates intracellular Ca2+ in cardiac myocytes and is up-regulated in dystrophic cardiomyopathy
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NOS1AP modulates intracellular Ca2+ in cardiac myocytes and is up-regulated in dystrophic cardiomyopathy

机译：NOS1AP调节心肌细胞中的细胞内Ca2 +并在营养不良性心肌病中上调

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NOS1AP gene (nitric oxide synthase 1-adaptor protein) is strongly associated with abnormalities in the QT interval of the electrocardiogram and with sudden cardiac death. To determine the role of NOS1AP in the physiology of the cardiac myocyte, we assessed the impact of silencing NOS1AP, using siRNA, on [Casup2+/sup]subi/sub transients in neonatal cardiomyocytes. In addition, we examined the co-localization of NOS1AP with cardiac ion channels, and finally, evaluated the expression of NOS1AP in a mouse model of dystrophic cardiomyopathy. Using siRNA, NOS1AP levels were reduced to ~30% of the control levels (p<0.05). NOS1AP silencing in cardiac myocytes reduced significantly the amplitude of electrically evoked calcium transients (p<0.05) and the degree of S-nitrosylation of the cells (p<0.05). Using confocal microscopy, we evaluated NOS1AP subcellular location and interactions with other proteins by co-localization analysis. NOS1AP showed a high degree of co-localization with the L-type calcium channel and the inwardly rectifying potassium channel Kir3.1, a low degree of co-localization with the ryanodine receptor (RyR2) and alfa-sarcomeric actin and no co-localization with connexin 43, suggesting functionally relevant interactions with the ion channels that regulate the action potential duration. Finally, using immunofluorescence and Western blotting, we observed that in mice with dystrophic cardiomyopathy, NOS1AP was significantly up-regulated (p<0.05). These results suggest for a role of NOS1AP on cardiac arrhythmias, acting on the L-type calcium channel, and potassium channels, probably through S-nitrosylation.
机译：NOS1AP基因（一氧化氮合酶1适配器蛋白）与心电图QT间隔的异常和心源性猝死密切相关。为了确定NOS1AP在心肌细胞生理中的作用，我们使用siRNA评估了沉默NOS1AP对新生心肌细胞[Ca 2 + ] i 瞬变的影响。此外，我们检查了NOS1AP与心脏离子通道的共定位，最后评估了营养不良性心肌病小鼠模型中NOS1AP的表达。使用siRNA，NOS1AP水平降至对照水平的〜30％（p＆＃x0003c; 0.05）。心肌细胞中的NOS1AP沉默显着降低了电诱发钙瞬变的幅度（p＆＃x0003c; 0.05）和细胞的S-亚硝基化程度（p＆＃x0003c; 0.05）。使用共聚焦显微镜，我们通过共定位分析评估了NOS1AP的亚细胞定位以及与其他蛋白质的相互作用。 NOS1AP与L型钙通道和向内整流的钾通道Kir3.1高度共定位，与ryanodine受体（RyR2）和α-肌氨酸肌动蛋白的共定位程度较低，而没有共定位与连接蛋白43结合，表明与调节动作电位持续时间的离子通道在功能上相关的相互作用。最后，使用免疫荧光和蛋白质印迹，我们观察到在营养不良性心肌病的小鼠中，NOS1AP明显上调（p＆＃x0003c; 0.05）。这些结果表明，NOS1AP可能通过S-亚硝基化作用对心律不齐起作用，作用于L型钙通道和钾通道。

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