Modeling Secondary Iron Overload Cardiomyopathy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
Modeling Secondary Iron Overload Cardiomyopathy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
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DOI：
10.1016/j.celrep.2020.107886
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发表时间：
2020-07-14
期刊：
影响因子：
8.8
通讯作者：
Wu JC
中科院分区：
文献类型：
--
作者：
Rhee JW;Yi H;Thomas D;Lam CK;Belbachir N;Tian L;Qin X;Malisa J;Lau E;Paik DT;Kim Y;Choi BS;Sayed N;Sallam K;Liao R;Wu JC
心脏中过多的铁积聚会导致铁过载心肌病（IOC），最初表现为舒张功能障碍和心律失常，但如果不及时治疗，会进展为收缩功能障碍和终末期心力衰竭。然而，与铁相关的心脏损伤的机制以及铁如何在人类心肌细胞中积累尚不清楚。在此，我们利用人类诱导多能干细胞来源的心肌细胞 (iPSC-CM) 建立了 IOC 模型并筛选了挽救铁超载表型的药物。过量铁暴露下的人类 iPSC-CM 重现了早期 IOC，包括氧化应激、心律失常和收缩功能障碍。我们发现铁诱导的钙动力学变化在心肌细胞功能失调中发挥着关键作用。我们发现依布硒啉（ebselen）是一种选择性 DMT1 抑制剂和抗氧化剂，可以预防观察到的铁过载表型，支持 DMT1 在人体心肌铁吸收中的作用。这些结果表明依布硒啉可能是治疗继发性铁超负荷患者的潜在预防和治疗药物。
Excessive iron accumulation in the heart causes iron overload cardiomyopathy (IOC) which initially presents as diastolic dysfunction and arrhythmia but progresses to systolic dysfunction and end-stage heart failure when left untreated. However, the mechanisms of iron-related cardiac injury and how iron accumulates in human cardiomyocytes are not well understood. Herein, using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we modeled IOC and screened for drugs to rescue the iron overload phenotypes. Human iPSC-CMs under excess iron exposure recapitulate early-stage IOC, including oxidative stress, arrhythmia, and contractile dysfunction. We found that iron-induced changes in calcium kinetics play a critical role in dysregulation of cardiomyocyte functions. We identified that ebselen, a selective DMT1 inhibitor and antioxidant, could prevent the observed iron overload phenotypes, supporting the role of DMT1 in iron uptake into the human myocardium. These results suggest that ebselen may be a potential preventive and therapeutic agent for treating patients with secondary iron overload.
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影响因子：
5
作者：
Khamseekaew, Juthamas;Kumfu, Sirinart;Chattipakorn, Nipon
通讯作者：
Chattipakorn, Nipon
DOI：
10.1007/978-1-62703-511-8_7
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Churko JM;Burridge PW;Wu JC
通讯作者：
Wu JC
影响因子：
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Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
20.1
作者：
Chang HC;Shapiro JS;Ardehali H
通讯作者：
Ardehali H
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.