Stanford Cardiovascular Institute, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford, CA 94305, USA.
Stanford Cardiovascular Institute, Stanford, CA 94305, USA.
Cell Rep. 2020 Jul 14;32(2):107886. doi: 10.1016/j.celrep.2020.107886.
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.
心脏中铁元素过度积累会导致铁过载心肌病（IOC），如果不加以治疗，最初表现为舒张功能障碍和心律失常，进而发展为收缩功能障碍和终末期心力衰竭。然而，铁相关性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，我们使用人类诱导多能干细胞衍生的心肌细胞（iPSC-CMs），模拟 IOC 并筛选药物以挽救铁过载表型。暴露于过量铁的人类 iPSC-CMs 再现了早期 IOC，包括氧化应激、心律失常和收缩功能障碍。我们发现，钙动力学的铁诱导变化在 CM 功能失调中起着关键作用。我们发现，依布硒啉是一种选择性二价金属转运蛋白 1（DMT1）抑制剂和抗氧化剂，可预防观察到的铁过载表型，这支持 DMT1 在铁摄取进入人类心肌中的作用。这些结果表明，依布硒啉可能是治疗继发性铁过载患者的一种有潜力的预防和治疗药物。
