Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure

被引:155
作者
Haddad, Saba [1 ,2 ]
Wang, Yong [1 ,2 ]
Galy, Bruno [3 ,4 ]
Korf-Klingebiel, Mortimer [1 ,2 ]
Hirsch, Valentin [1 ,2 ]
Baru, Abdul M. [1 ,2 ]
Rostami, Fatemeh [1 ,2 ]
Reboll, Marc R. [1 ,2 ]
Heineke, Joerg [2 ]
Floegel, Ulrich [5 ]
Groos, Stephanie [6 ]
Renner, Andre [7 ]
Toischer, Karl [8 ]
Zimmermann, Fabian [9 ]
Engeli, Stefan [10 ]
Jordan, Jens [10 ]
Bauersachs, Johann [2 ]
Hentze, Matthias W. [3 ]
Wollert, Kai C. [1 ,2 ]
Kempf, Tibor [1 ,2 ]
机构
[1] Hannover Med Sch, Div Mol & Translat Cardiol, Carl Neuberg Str 1, D-30625 Hannover, Germany
[2] Hannover Med Sch, Dept Cardiol & Angiol, Carl Neuberg Str 1, D-30625 Hannover, Germany
[3] European Mol Biol Lab, Meyerhofstr 1, D-69117 Heidelberg, Germany
[4] German Canc Res Ctr, Div Virus Associated Carcinogenesis, Neuenheimer Feld 280, D-69120 Heidelberg, Germany
[5] Univ Dusseldorf, Dept Mol Cardiol, Univ Str 1, D-40225 Dusseldorf, Germany
[6] Hannover Med Sch, Inst Cell Biol, Carl Neuberg Str 1, D-30625 Hannover, Germany
[7] Univ Bochum, Dept Thorac & Cardiovasc Surg, Georgstr 11, D-32545 Bad Oeynhausen, Germany
[8] Univ Gottingen, Dept Cardiol & Pneumol, Robert Koch Str 40, D-37075 Gottingen, Germany
[9] Leibniz Univ Hannover, Dept Analyt Chem, Callinstr 1, D-30167 Hannover, Germany
[10] Hannover Med Sch, Inst Clin Pharmacol, Carl Neuberg Str 1, D-30625 Hannover, Germany
关键词
Iron deficiency; Heart failure; Energy metabolism; Extracellular flux analysis; P-31-Magnetic resonance spectroscopy; FERRIC CARBOXYMALTOSE; DEFICIENCY; CARDIOMYOPATHY; METABOLISM; ANEMIA; BIOGENESIS; MECHANISMS; DISORDERS; DISEASE; HEME;
D O I
10.1093/eurheartj/ehw333
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 anaemia Methods 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 content Conclusions 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.
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收藏
页码:362 / +
页数:12
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