Mechanism of As2O3-Induced Action Potential Prolongation and Using hiPS-CMs to Evaluate the Rescue Efficacy of Drugs With Different Rescue Mechanism
Mechanism of As2O3-Induced Action Potential Prolongation and Using hiPS-CMs to Evaluate the Rescue Efficacy of Drugs With Different Rescue Mechanism
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As2O3诱导动作电位延长的机制及利用hiPS-CM评价不同解救机制药物的解救效果
DOI：
10.1093/toxsci/kfx098
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发表时间：
2017-08
影响因子：
3.8
通讯作者：
Li Baoxin
中科院分区：
文献类型：
--
作者：
Yan Meng;Feng Lifang;Shi Yanhui;Wang Junnan;Liu Yan;Li Fengmei;Li Baoxin
三氧化二砷（As 2 O3）是近几十年来治疗急性早幼粒细胞白血病的一个突破性进展。然而，心脏毒性，特别是长QT综合征（LQTS）已成为As 2 O3治疗过程中最重要的问题。这种不良反应背后的特征性机制是抑制心脏hERG通道运输和增加心脏钙电流。本研究发现了一种新的As_2O_3致心脏毒性的机制，即在使用布雷菲德菌素A（Brefeldin A，BFA）阻断蛋白运输后，As_2O_3加速溶酶体降解质膜上的hERG。随后，我们探索了As 2 O3诱导的LQTS的药物拯救策略，发现4种治疗药物通过3种不同的途径发挥拯救作用：非索非那定和阿司咪唑通过促进As 2 O3孵育后通道伴侣蛋白的形成促进hERG的运输;雷诺嗪减缓As 2 O3存在下的hERG降解;白藜芦醇对As 2 O3引发的钙电流增加表现出显著的衰减作用。此外，我们使用人类诱导的多能干细胞衍生的心肌细胞（hiPS-CM），以评估上述药物对As 2 O3诱导的动作电位时程（APD）延长的拯救作用，并证明非索非那定和白藜芦醇显着改善APD延长。这些观察结果表明，药理学分子伴侣，如非索非那定和白藜芦醇可能有可能防止As 2 O3的心脏毒性。
Arsenic trioxide (As2O3) has been verified as a breakthrough in the management of acute promyelocytic leukemia in recent decades. However, cardiotoxicity, especially long QT syndrome (LQTS) has become the most important issue during As2O3 treatment. The characterized mechanisms behind this adverse effect are inhibition of cardiac hERG channel trafficking and increase of cardiac calcium currents. In our study, we found a new pathway underlying As2O3-induced cardiotoxicity that As2O3 accelerates lysosomal degradation of hERG on plasma membrane after using brefeldin A (BFA) to block protein trafficking. Then we explored pharmacological rescue strategies on As2O3-induced LQTS, and found that 4 therapeutic agents exert rescue efficacy via 3 different pathways: fexofenadine and astemizole facilitate hERG trafficking via promotion of channel-chaperone formation after As2O3 incubation; ranolazine slows hERG degradation in the presence of As2O3; and resveratrol shows significant attenuation on calcium current increase triggered by As2O3. Moreover, we used human-induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) to evaluate the rescue effects of the above agents on As2O3-induced prolongation of action potential duration (APD) and demonstrated that fexofenadine and resveratrol significantly ameliorate the prolonged APD. These observations suggested that pharmacological chaperone like fexofenadine and resveratrol might have the potential to protect against the cardiotoxicity of As2O3.
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DOI：
10.1016/j.yjmcc.2007.03.024
发表时间：
2006-02
影响因子：
3.1
作者：
通讯作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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