Modeling Secondary Iron Overload Cardiomyopathy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

被引:34
作者
Rhee, June-Wha [1 ,2 ]
Yi, Hyoju [1 ]
Thomas, Dilip [1 ]
Lam, Chi Keung [1 ]
Belbachir, Nadjet [1 ]
Tian, Lei [1 ]
Qin, Xulei [1 ]
Malisa, Jessica [1 ]
Lau, Edward [1 ]
Paik, David T. [1 ]
Kim, Youngkyun [1 ]
Choi, Beatrice SeungHye [1 ]
Sayed, Nazish [1 ]
Sallam, Karim [1 ,2 ]
Liao, Ronglih [1 ,2 ]
Wu, Joseph C. [1 ,2 ,3 ,4 ]
机构
[1] Stanford Cardiovasc Inst, Stanford, CA 94305 USA
[2] Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA
[3] Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA
[4] Stanford Univ, Dept Radiol, Sch Med, Stanford, CA 94305 USA
来源
CELL REPORTS | 2020年 / 32卷 / 02期
关键词
EBSELEN; TRANSFERRIN; EXPRESSION; CHELATOR; DISEASE; PATIENT; HEART;
D O I
10.1016/j.celrep.2020.107886
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 model IOC and screen 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 find that iron-induced changes in calcium kinetics play a critical role in dysregulation of CM functions, We identify that ebselen, a selective divalent metal transporter 1 (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.
引用
收藏
页数:13
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