Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure
Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure
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DOI：
10.1093/eurheartj/ehw333
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发表时间：
2017-02-01
影响因子：
39.3
通讯作者：
Kempf, Tibor
中科院分区：
文献类型：
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作者：
Haddad, Saba;Wang, Yong;Kempf, Tibor
AIMS铁缺乏(ID)与心力衰竭(HF)的不良后果有关，但其潜在机制尚不完全清楚。细胞内铁的可利用性由两个mRNA结合的铁调节蛋白(IRPS)保证，即IRP1和IRP2。我们建立了心肌细胞靶向缺失Irp1和Irp2的小鼠，以探索ID在心脏中的功能意义，而不依赖于全身性ID和贫血方法和结果IRP靶向小鼠心肌细胞中铁含量减少。这些动物没有贫血，在基线条件下也没有表现出表型。然而，以IRP为靶点的小鼠无法提高左心室(LV)收缩功能，以应对急性多巴酚丁胺挑战。心肌梗死后，以IRP为靶点的小鼠出现了更严重的左心功能不全，并增加了心衰死亡率。从机械上讲，IRP靶向小鼠左室线粒体电子传输链的含铁硫簇复合体I的活性降低。体外细胞外流量分析表明，IRP靶向心肌细胞线粒体呼吸在基线水平保持不变，但不能增加多巴酚丁胺的反应。体内P-31磁共振波谱显示，IRP靶向小鼠在多巴酚丁胺应激过程中，左室磷酸肌酸/三磷酸腺苷比值下降，而对照组小鼠保持稳定。静脉注射碳化麦芽糖铁可补充心肌铁储备，恢复线粒体呼吸能力和肌力储备，并减轻心肌梗死后的不良重构，但对照组小鼠没有。电泳迁移率改变分析显示，晚期心衰患者左心室组织中IRP活性显著降低，且左室组织铁含量降低。结论心肌细胞内ID损害了心肌细胞的线粒体膜呼吸和对急、慢性负荷增加的适应。补充铁可以恢复缺铁心脏的能量储备和功能。
Aims Iron deficiency (ID) is associated with adverse outcomes in heart failure (HF) but the underlying mechanisms are incompletely understood. Intracellular iron availability is secured by two mRNA-binding iron-regulatory proteins (IRPs), IRP1 and IRP2. We generated mice with a cardiomyocyte-targeted deletion of Irp1 and Irp2 to explore the functional implications of ID in the heart independent of systemic ID and anaemiaMethods and results Iron content in cardiomyocytes was reduced in Irp-targeted mice. The animals were not anaemic and did not show a phenotype under baseline conditions. Irp-targeted mice, however, were unable to increase left ventricular (LV) systolic function in response to an acute dobutamine challenge. After myocardial infarction, Irp-targeted mice developed more severe LV dysfunction with increased HF mortality. Mechanistically, the activity of the iron-sulphur cluster-containing complex I of the mitochondrial electron transport chain was reduced in left ventricles from Irp-targeted mice. As demonstrated by extracellular flux analysis in vitro, mitochondrial respiration was preserved at baseline but failed to increase in response to dobutamine in Irp-targeted cardiomyocytes. As shown by P-31-magnetic resonance spectroscopy in vivo, LV phosphocreatine/ATP ratio declined during dobutamine stress in Irp-targeted mice but remained stable in control mice. Intravenous injection of ferric carboxymaltose replenished cardiac iron stores, restored mitochondrial respiratory capacity and inotropic reserve, and attenuated adverse remodelling after myocardial infarction in Irp-targeted mice but not in control mice. As shown by electrophoretic mobility shift assays, IRP activity was significantly reduced in LV tissue samples from patients with advanced HF and reduced LV tissue iron contentConclusions ID in cardiomyocytes impairs mitoch/ondrial respiration and adaptation to acute and chronic increases in workload. Iron supplementation restores cardiac energy reserve and function in iron-deficient hearts.