Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome.
Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome.
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DOI：
10.1126/scitranslmed.3003623
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发表时间：
2012-04-25
影响因子：
17.1
通讯作者：
Lin RZ
中科院分区：
文献类型：
--
作者：
Lu Z;Wu CY;Jiang YP;Ballou LM;Clausen C;Cohen IS;Lin RZ
许多药物，包括一些常用药物，可导致心律失常和猝死，如心电图中QT间期延长。由药物诱导的长QT综合征引起的心律失常被认为主要是由于延迟整流钾离子（K+）电流IKr的减少。在这里，我们报告了一种机制，药物诱导的QT间期延长，涉及多个离子电流的变化引起的减少磷酸肌醇3-激酶（PI 3 K）信号。用酪氨酸激酶或PI 3 Ks抑制剂治疗犬心肌细胞引起动作电位持续时间增加，可通过细胞内输注磷脂酰肌醇3，4，5-三磷酸逆转。抑制剂降低延迟整流钾电流IKr和IKs，L型钙离子电流伊卡，L和钠离子峰值电流INa，增加持续性钠离子电流INaP。犬心室动作电位的计算机模拟表明，药物引起的任何一个电流的变化占动作电位时程增加的不到50%。缺乏PI 3 K p110α催化亚基的小鼠心脏表现出动作电位和QT间期延长，这至少部分是INaP增加的结果。这些结果表明，通过酪氨酸激酶抑制直接或间接下调PI 3 K信号转导通过影响多个离子通道来延长QT间期。这种机制可以解释为什么临床使用的一些酪氨酸激酶抑制剂与危及生命的心律失常的风险增加有关。
Many drugs, including some commonly used medications, can cause abnormal heart rhythms and sudden death, as manifest by a prolonged QT interval in the electrocardiogram. Cardiac arrhythmias caused by drug-induced long QT syndrome are thought to result mainly from reductions in the delayed rectifier potassium ion (K+) current IKr. Here, we report a mechanism for drug-induced QT prolongation that involves changes in multiple ion currents caused by a decrease in phosphoinositide 3-kinase (PI3K) signaling. Treatment of canine cardiac myocytes with inhibitors of tyrosine kinases or PI3Ks caused an increase in action potential duration that was reversed by intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate. The inhibitors decreased the delayed rectifier K+ currents IKr and IKs, the L-type calcium ion (Ca2+) current ICa,L, and the peak sodium ion (Na+) current INa and increased the persistent Na+ current INaP. Computer modeling of the canine ventricular action potential showed that the drug-induced change in any one current accounted for less than 50% of the increase in action potential duration. Mouse hearts lacking the PI3K p110α catalytic subunit exhibited a prolonged action potential and QT interval that were at least partly a result of an increase in INaP. These results indicate that down-regulation of PI3K signaling directly or indirectly via tyrosine kinase inhibition prolongs the QT interval by affecting multiple ion channels. This mechanism may explain why some tyrosine kinase inhibitors in clinical use are associated with increased risk of life-threatening arrhythmias.
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影响因子：
4.8
作者：
Fan, GF;Jiang, YP;Lin, RZ
通讯作者：
Lin, RZ
影响因子：
158.5
作者：
Kantarjian, Hagop;Giles, Francis;Ottmann, Oliver G.
通讯作者：
Ottmann, Oliver G.
影响因子：
37.8
作者：
Lu Z;Jiang YP;Wang W;Xu XH;Mathias RT;Entcheva E;Ballou LM;Cohen IS;Lin RZ
通讯作者：
Lin RZ
影响因子：
5.7
作者：
Maira, Sauveur-Michel;Stauffer, Frederic;Garcia-Echeverria, Carlos
通讯作者：
Garcia-Echeverria, Carlos
影响因子：
5.5
作者：
Cockerill, S. L.;Tobin, A. B.;Mitcheson, J. S.
通讯作者：
Mitcheson, J. S.