Drug-Mediated Shortening of Action Potentials in LQTS2 Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
Drug-Mediated Shortening of Action Potentials in LQTS2 Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
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DOI：
10.1089/scd.2017.0172
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发表时间：
2017-12-01
影响因子：
4
通讯作者：
Denning C
中科院分区：
文献类型：
--
作者：
Duncan G;Firth K;George V;Hoang MD;Staniforth A;Smith G;Denning C
人类诱导多能干细胞（hipsc）衍生的心肌细胞（CMs）现在是一种建立心脏遗传疾病模型的成熟模式。对于长QT综合征（LQTS）尤其如此，它是由离子通道功能紊乱引起的，可导致昏厥、恶性心律失常和心源性猝死。LQTS2是由KCNH2突变引起的，KCNH2是一种基因，其蛋白产物有助于IKr（也称为HERG），这是CMs中主要的复极钾电流。β受体阻滞剂是LQTS患者的主要治疗药物，其作用是降低心率和心律失常。然而，它们对大约四分之一的LQTS2患者无效，部分原因是它们不能纠正病症的定义特征，即QT间期过长。由于需要新的治疗方法，在本报告中，我们对一名基因和临床诊断为LQTS2的患者的皮肤成纤维细胞进行了活检。通过制作LQTS-hiPSC-CMs，我们评估了不同药物对动作电位持续时间（APD）的影响，APD被用作QT间期的体外替代指标。毫不奇怪，患者自己的β受体阻滞剂药物心得安对LQTS-hiPSC-CMs的APD有边际效应。然而，通过直接通道结合或通过PPARδ/蛋白14-3-3 epsilon/HERG途径间接介导增强IKr电流的化合物可显著降低APD高达19%。药物诱导的替代钾电流（IKATP）增强也使APD降低了21%。这项研究证明了LQTS-hiPSC-CMs在评估药物是否可以缩短APD方面的效用，重要的是，表明PPARδ激动剂可能会形成一类新的治疗这种疾病的药物。
Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) are now a well-established modality for modeling genetic disorders of the heart. This is especially so for long QT syndrome (LQTS), which is caused by perturbation of ion channel function, and can lead to fainting, malignant arrhythmias and sudden cardiac death. LQTS2 is caused by mutations in KCNH2, a gene whose protein product contributes to IKr (also known as HERG), which is the predominant repolarizing potassium current in CMs. β-blockers are the mainstay treatment for patients with LQTS, functioning by reducing heart rate and arrhythmogenesis. However, they are not effective in around a quarter of LQTS2 patients, in part, because they do not correct the defining feature of the condition, which is excessively prolonged QT interval. Since new therapeutics are needed, in this report, we biopsied skin fibroblasts from a patient who was both genetically and clinically diagnosed with LQTS2. By producing LQTS-hiPSC-CMs, we assessed the impact of different drugs on action potential duration (APD), which is used as an in vitro surrogate for QT interval. Not surprisingly, the patient's own β-blocker medication, propranolol, had a marginal effect on APD in the LQTS-hiPSC-CMs. However, APD could be significantly reduced by up to 19% with compounds that enhanced the IKr current by direct channel binding or by indirect mediation through the PPARδ/protein 14-3-3 epsilon/HERG pathway. Drug-induced enhancement of an alternative potassium current, IKATP, also reduced APD by up to 21%. This study demonstrates the utility of LQTS-hiPSC-CMs in evaluating whether drugs can shorten APD and, importantly, shows that PPARδ agonists may form a new class of therapeutics for this condition.
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影响因子：
2.9
作者：
FLEISHAKER, JC;ANDREADIS, NA;WRIGHT, CE
通讯作者：
WRIGHT, CE
影响因子：
48
作者：
Burridge, Paul W.;Matsa, Elena;Shukla, Praveen;Lin, Ziliang C.;Churko, Jared M.;Ebert, Antje D.;Lan, Feng;Diecke, Sebastian;Huber, Bruno;Mordwinkin, Nicholas M.;Plews, Jordan R.;Abilez, Oscar J.;Cui, Bianxiao;Gold, Joseph D.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.
影响因子：
24
作者：
Abu-Zeitone, Abeer;Peterson, Derick R.;Moss, Arthur J.
通讯作者：
Moss, Arthur J.
DOI：
10.1007/978-1-4939-6588-5_2
发表时间：
2017-01-01
期刊：
CARDIAC GENE THERAPY: METHODS AND PROTOCOLS
影响因子：
--
作者：
Fechner, Henry;Vetter, Roland;Poller, Wolfgang
通讯作者：
Poller, Wolfgang
对人过氧化物酶体增殖物激活受体三角洲（PPAR-DELTA）选择性配体结合的结构见解。
影响因子：
3.7
作者：
Batista FA;Trivella DB;Bernardes A;Gratieri J;Oliveira PS;Figueira AC;Webb P;Polikarpov I
通讯作者：
Polikarpov I