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

Cell Reports
June-Wha RheeJoseph C Wu

Abstract

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.

Citations

Jan 22, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Chi Keung Lam, Joseph C Wu
Jan 9, 2021·Circulation. Arrhythmia and Electrophysiology·Natthaphat Siri-AngkulLai-Hua Xie
Apr 26, 2021·Journal of Molecular and Cellular Cardiology·Sangkyun ChoJoseph C Wu
Apr 13, 2021·Biomarkers : Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals·Karolina WeinmannMirjam Keßler
Jun 22, 2021·ACS Biomaterials Science & Engineering·Diogo TelesGordana Vunjak-Novakovic

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