Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function.
Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function.
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DOI：
10.1002/ejhf.1154
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发表时间：
2018-05
影响因子：
18.2
通讯作者：
van der Meer P
中科院分区：
文献类型：
--
作者：
Hoes MF;Grote Beverborg N;Kijlstra JD;Kuipers J;Swinkels DW;Giepmans BNG;Rodenburg RJ;van Veldhuisen DJ;de Boer RA;van der Meer P
铁缺乏在心力衰竭患者中很常见，并与心功能不佳和较高的死亡率有关。在人类环境中，缺铁如何在细胞水平上损害心脏功能尚不清楚。本研究旨在探讨缺铁和缺铁对人心肌细胞的直接影响。人胚胎干细胞来源的心肌细胞通过与铁络合剂去铁胺(DFO)孵育来耗尽铁。线粒体呼吸通过海马Mito应激试验测定，并根据基本方法使用视频分析直接量化收缩。用分光光度法测线粒体呼吸链复合体的活性。铁缺乏4天导致铁蛋白下降84%(P<；0.0001)，转铁蛋白受体1和二价金属转运蛋白1的基因表达显著增加(P<；0.001)。铁缺乏的心肌细胞线粒体功能降低，尤其是三磷酸腺苷连接的呼吸和呼吸储备受损(P<；0.0001)。铁缺乏影响线粒体的功能，是通过降低含有络合物I、II和III的铁硫簇的活性，而不是络合物IV和V的活性来实现的。缺铁使细胞的三磷酸腺苷水平降低了74%(P<；0.0001)，收缩能力降低了43%(P<；0.05)。收缩和舒张期最大血流速度分别下降了%和85%(P均<0.001)。补充转铁蛋白结合铁在3天内恢复了功能和形态的异常。缺铁直接影响人的心肌细胞功能，损害线粒体呼吸，降低收缩和松弛能力。细胞内铁水平的恢复可以逆转这些影响。
Iron deficiency is common in patients with heart failure and associated with a poor cardiac function and higher mortality. How iron deficiency impairs cardiac function on a cellular level in the human setting is unknown. This study aims to determine the direct effects of iron deficiency and iron repletion on human cardiomyocytes. Human embryonic stem cell‐derived cardiomyocytes were depleted of iron by incubation with the iron chelator deferoxamine (DFO). Mitochondrial respiration was determined by Seahorse Mito Stress test, and contractility was directly quantified using video analyses according to the BASiC method. The activity of the mitochondrial respiratory chain complexes was examined using spectrophotometric enzyme assays. Four days of iron depletion resulted in an 84% decrease in ferritin (P < 0.0001) and significantly increased gene expression of transferrin receptor 1 and divalent metal transporter 1 (both P < 0.001). Mitochondrial function was reduced in iron‐deficient cardiomyocytes, in particular ATP‐linked respiration and respiratory reserve were impaired (both P < 0.0001). Iron depletion affected mitochondrial function through reduced activity of the iron–sulfur cluster containing complexes I, II and III, but not complexes IV and V. Iron deficiency reduced cellular ATP levels by 74% (P < 0.0001) and reduced contractile force by 43% (P < 0.05). The maximum velocities during both systole and diastole were reduced by 64% and 85%, respectively (both P < 0.001). Supplementation of transferrin‐bound iron recovered functional and morphological abnormalities within 3 days. Iron deficiency directly affects human cardiomyocyte function, impairing mitochondrial respiration, and reducing contractility and relaxation. Restoration of intracellular iron levels can reverse these effects.
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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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