Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders.
Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders.
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DOI：
10.1038/s41598-017-00413-3
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发表时间：
2017-03-23
影响因子：
4.6
通讯作者：
Rosenzweig A
中科院分区：
文献类型：
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作者：
Bezzerides VJ;Zhang A;Xiao L;Simonson B;Khedkar SA;Baba S;Ottaviano F;Lynch S;Hessler K;Rigby AC;Milan D;Das S;Rosenzweig A
钠流量的改变在心律失常的发病机制中起着重要作用，也可能促进心肌病的发展。我们最近证实了血清和糖皮质激素调节的激酶-1(SGK1)对心脏电压门控钠通道NaV1.5的调节起到了关键作用。在心脏中，SGK1的激活导致峰值和晚期钠电流的显着增加，导致动作电位时程的延长和心律失常的增加。在这里，我们证明了SGK1直接调节NaV1.5通道功能，在遗传性长QT综合征斑马鱼模型中，SGK1的基因抑制拯救了长QT表型。利用计算机辅助药物发现和体外激酶分析，我们鉴定了一类新的SGK1抑制剂。我们的SGK1先导抑制剂(5377051)选择性地抑制培养的心肌细胞中的SGK1，并抑制SGK1特异性靶点的磷酸化以及前列腺癌LNCaP细胞的增殖。最后，5377051可以逆转SGK1对NAV1.5的S效应，并缩短NAV1.5功能获得突变(长QT3综合征)患者诱导的多能干细胞来源的心肌细胞的动作电位时程。我们的数据表明，SGK1抑制剂在治疗心律失常方面值得进一步研究。
Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1). Activation of SGK1 in the heart causes a marked increase in both the peak and late sodium currents leading to prolongation of the action potential duration and an increased propensity to arrhythmia. Here we show that SGK1 directly regulates NaV1.5 channel function, and genetic inhibition of SGK1 in a zebrafish model of inherited long QT syndrome rescues the long QT phenotype. Using computer-aided drug discovery coupled with in vitro kinase assays, we identified a novel class of SGK1 inhibitors. Our lead SGK1 inhibitor (5377051) selectively inhibits SGK1 in cultured cardiomyocytes, and inhibits phosphorylation of an SGK1-specific target as well as proliferation in the prostate cancer cell line, LNCaP. Finally, 5377051 can reverse SGK1’s effects on NaV1.5 and shorten the action potential duration in induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a patient with a gain-of-function mutation in Nav 1.5 (Long QT3 syndrome). Our data suggests that SGK1 inhibitors warrant further investigation in the treatment of cardiac arrhythmias.