RESUMEN
Chronic kidney disease and anaemia are common in heart failure (HF) and are associated with a worse prognosis in these patients. Iron deficiency is also common in patients with HF and increases the risk of morbidity and mortality, regardless of the presence or absence of anaemia. While the treatment of anaemia with erythropoiesis-stimulating agents in patients with HF have failed to show a benefit in terms of morbidity and mortality, treatment with IV iron in patients with HF and reduced ejection fraction and iron deficiency is associated with clinical improvement. In a posthoc analysis of a clinical trial, iron therapy improved kidney function in patients with HF and iron deficiency. In fact, the European Society of Cardiology's recent clinical guidelines on HF suggest that in symptomatic patients with reduced ejection fraction and iron deficiency, treatment with IV ferric carboxymaltose should be considered to improve symptoms, the ability to exercise and quality of life. Iron plays a key role in oxygen storage (myoglobin) and in energy metabolism, and there are pathophysiological bases that explain the beneficial effect of IV iron therapy in patients with HF. All these aspects are reviewed in this article.
Asunto(s)
Compuestos Férricos/uso terapéutico , Insuficiencia Cardíaca/etiología , Deficiencias de Hierro , Maltosa/análogos & derivados , Anemia Ferropénica/tratamiento farmacológico , Anemia Ferropénica/etiología , Anemia Ferropénica/fisiopatología , Animales , Modelos Animales de Enfermedad , Compuestos Férricos/administración & dosificación , Tasa de Filtración Glomerular , Insuficiencia Cardíaca/tratamiento farmacológico , Hematínicos/uso terapéutico , Humanos , Infusiones Intravenosas , Proteínas Reguladoras del Hierro/deficiencia , Proteínas Reguladoras del Hierro/fisiología , Maltosa/administración & dosificación , Maltosa/uso terapéutico , Metaanálisis como Asunto , Ratones , Estudios Multicéntricos como Asunto , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatología , Volumen Sistólico/efectos de los fármacosRESUMEN
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 31P-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 mitochondrial respiration and adaptation to acute and chronic increases in workload. Iron supplementation restores cardiac energy reserve and function in iron-deficient hearts.
Asunto(s)
Insuficiencia Cardíaca/prevención & control , Deficiencias de Hierro , Proteínas Reguladoras del Hierro/fisiología , Miocitos Cardíacos/metabolismo , Animales , Cardiotónicos/farmacología , Dopamina/farmacología , Compuestos Férricos/farmacología , Ferritinas/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Humanos , Hierro/metabolismo , Proteínas Reguladoras del Hierro/deficiencia , Angiografía por Resonancia Magnética , Maltosa/análogos & derivados , Maltosa/farmacología , Mitocondrias Cardíacas/fisiología , Fenotipo , ARN Mensajero/fisiología , Función Ventricular Izquierda/fisiologíaRESUMEN
No disponible
Asunto(s)
Humanos , Hemocromatosis/diagnóstico , Hemocromatosis/tratamiento farmacológico , Sobrecarga de Hierro/fisiopatología , Trastornos del Metabolismo del Hierro/fisiopatología , Proteínas Reguladoras del Hierro/deficiencia , Flebotomía , Quelantes del Hierro/uso terapéutico , Eliminación de Componentes Sanguíneos , Estudios de Asociación GenéticaRESUMEN
Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are two cytosolic proteins that maintain cellular iron homeostasis by binding to RNA stem loops known as iron responsive elements (IREs) that are found in the untranslated regions of target mRNAs that encode proteins involved in iron metabolism. IRPs modify the expression of iron metabolism genes, and global and tissue-specific knockout mice have been made to evaluate the physiological significance of these iron regulatory proteins (Irps). Here, we will discuss the results of the studies that have been performed with mice engineered to lack the expression of one or both Irps and made in different strains using different methodologies. Both Irp1 and Irp2 knockout mice are viable, but the double knockout (Irp1(-/-)Irp2(-/-)) mice die before birth, indicating that these Irps play a crucial role in maintaining iron homeostasis. Irp1(-/-) mice develop polycythemia and pulmonary hypertension, and when these mice are challenged with a low iron diet, they die early of abdominal hemorrhages, suggesting that Irp1 plays an essential role in erythropoiesis and in the pulmonary and cardiovascular systems. Irp2(-/-) mice develop microcytic anemia, erythropoietic protoporphyria and a progressive neurological disorder, indicating that Irp2 has important functions in the nervous system and erythropoietic homeostasis. Several excellent review articles have recently been published on Irp knockout mice that mainly focus on Irp1(-/-) mice (referenced in the introduction). In this review, we will briefly describe the phenotypes and physiological implications of Irp1(-/-) mice and discuss the phenotypes observed for Irp2(-/-) mice in detail with a particular emphasis on the neurological problems of these mice.
Asunto(s)
Trastornos del Metabolismo del Hierro/etiología , Proteínas Reguladoras del Hierro/deficiencia , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Trastornos del Metabolismo del Hierro/genética , Proteínas Reguladoras del Hierro/genética , Ratones , Ratones Transgénicos , Enfermedades Neurodegenerativas/genéticaRESUMEN
Mammalian iron metabolism is regulated systemically by the hormone hepcidin and cellularly by iron regulatory proteins (IRPs) that orchestrate a posttranscriptional regulatory network. Through ligand-inducible genetic ablation of both IRPs in the gut epithelium of adult mice, we demonstrate that IRP deficiency impairs iron absorption and promotes mucosal iron retention via a ferritin-mediated "mucosal block." We show that IRP deficiency does not interfere with intestinal sensing of body iron loading and erythropoietic iron need, but rather alters the basal expression of the iron-absorption machinery. IRPs thus secure sufficient iron transport across absorptive enterocytes by restricting the ferritin "mucosal block" and define a basal set point for iron absorption upon which IRP-independent systemic regulatory inputs are overlaid.
Asunto(s)
Enterocitos/metabolismo , Absorción Intestinal , Proteínas Reguladoras del Hierro/metabolismo , Hierro/metabolismo , Animales , Proteínas de Transporte de Catión/metabolismo , Ferritinas/genética , Ferritinas/metabolismo , Transporte Iónico , Proteínas Reguladoras del Hierro/deficiencia , Proteínas Reguladoras del Hierro/genética , Ratones , Mutación , Transcripción GenéticaRESUMEN
Mitochondria supply cells with ATP, heme, and iron sulfur clusters (ISC), and mitochondrial energy metabolism involves both heme- and ISC-dependent enzymes. Here, we show that mitochondrial iron supply and function require iron regulatory proteins (IRP), cytosolic RNA-binding proteins that control mRNA translation and stability. Mice lacking both IRP1 and IRP2 in their hepatocytes suffer from mitochondrial iron deficiency and dysfunction associated with alterations of the ISC and heme biosynthetic pathways, leading to liver failure and death. These results uncover a major role of the IRPs in cell biology: to ensure adequate iron supply to the mitochondrion for proper function of this critical organelle.
Asunto(s)
Proteínas Reguladoras del Hierro/metabolismo , Hierro/metabolismo , Mitocondrias/metabolismo , Animales , Metabolismo Energético , Hemo/biosíntesis , Proteína 1 Reguladora de Hierro/deficiencia , Proteína 1 Reguladora de Hierro/genética , Proteína 1 Reguladora de Hierro/metabolismo , Proteína 2 Reguladora de Hierro/deficiencia , Proteína 2 Reguladora de Hierro/genética , Proteína 2 Reguladora de Hierro/metabolismo , Proteínas Reguladoras del Hierro/deficiencia , Proteínas Reguladoras del Hierro/genética , Fallo Hepático/etiología , Fallo Hepático/metabolismo , Fallo Hepático/patología , Ratones , Ratones TransgénicosRESUMEN
Haemochromatosis is an iron-overload disorder with age-dependent oxidative stress and dysfunction in a variety of tissues. Mutations in HFE (histocompatability leucocyte antigen class I-like protein involved in iron homoeostasis) are responsible for most cases of haemochromatosis. We demonstrated recently that HFE is expressed exclusively in the basal membrane of RPE (retinal pigment epithelium). In the present study, we used Hfe-/- mice to examine ferritin levels (an indirect readout for iron levels) and morphological changes in retina. We found increased ferritin accumulation in retina in 18-month-old, but not in 2-month-old, mice with considerable morphological damage compared with age-matched controls. The retinal phenotype included hypertrophy and hyperplasia of RPE. RPE cells isolated from Hfe-/- mice exhibited a hyperproliferative phenotype. We also compared the gene expression profile between wild-type and Hfe-/- RPE cells by microarray analysis. These studies showed that many cell cycle-related genes were differentially regulated in Hfe-/- RPE cells. One of the genes up-regulated in Hfe-/- RPE cells was Slc7a11 (where Slc is solute carrier) which codes for the 'transporter proper' xCT in the heterodimeric cystine/glutamate exchanger (xCT/4F2hc). This transporter plays a critical role in cellular glutathione status and cell-cycle progression. We confirmed the microarrray data by monitoring xCT mRNA levels by RT (reverse transcription)-PCR and also by measuring transport function. We also found increased levels of glutathione and the transcription factor/cell-cycle promoter AP1 (activator protein 1) in Hfe-/- RPE cells. Wild-type mouse RPE cells and human RPE cell lines, when loaded with iron by exposure to ferric ammonium citrate, showed increased expression and activity of xCT, reproducing the biochemical phenotype observed with Hfe-/- RPE cells.
Asunto(s)
Sistema de Transporte de Aminoácidos y+/metabolismo , Proliferación Celular , Proteínas Reguladoras del Hierro/deficiencia , Proteínas de la Membrana/deficiencia , Epitelio Pigmentado de la Retina/citología , Epitelio Pigmentado de la Retina/metabolismo , Envejecimiento , Sistema de Transporte de Aminoácidos y+/genética , Animales , Células Cultivadas , Ferritinas/metabolismo , Glutatión/metabolismo , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/metabolismo , Proteínas Reguladoras del Hierro/metabolismo , Cinética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Regulación hacia ArribaRESUMEN
Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are mammalian proteins that register cytosolic iron concentrations and post-transcriptionally regulate expression of iron metabolism genes to optimize cellular iron availability. In iron-deficient cells, IRPs bind to iron-responsive elements (IREs) found in the mRNAs of ferritin, the transferrin receptor and other iron metabolism transcripts, thereby enhancing iron uptake and decreasing iron sequestration. IRP1 registers cytosolic iron status mainly through an iron-sulfur switch mechanism, alternating between an active cytosolic aconitase form with an iron-sulfur cluster ligated to its active site and an apoprotein form that binds IREs. Although IRP2 is homologous to IRP1, IRP2 activity is regulated primarily by iron-dependent degradation through the ubiquitin-proteasomal system in iron-replete cells. Targeted deletions of IRP1 and IRP2 in animals have demonstrated that IRP2 is the chief physiologic iron sensor. The physiological role of the IRP-IRE system is illustrated by (i) hereditary hyperferritinemia cataract syndrome, a human disease in which ferritin L-chain IRE mutations interfere with IRP binding and appropriate translational repression, and (ii) a syndrome of progressive neurodegenerative disease and anemia that develops in adult mice lacking IRP2. The early death of mouse embryos that lack both IRP1 and IRP2 suggests a central role for IRP-mediated regulation in cellular viability.
Asunto(s)
Catarata/metabolismo , Proteínas Reguladoras del Hierro/fisiología , Hierro/metabolismo , Animales , Catarata/genética , Ferritinas/genética , Ferritinas/metabolismo , Homeostasis , Humanos , Deficiencias de Hierro , Trastornos del Metabolismo del Hierro/genética , Trastornos del Metabolismo del Hierro/metabolismo , Proteínas Reguladoras del Hierro/deficiencia , Mutación , Conformación Proteica , ARN Mensajero/metabolismo , Elementos de Respuesta/fisiología , SíndromeRESUMEN
In mammals, iron regulatory proteins 1 and 2 (IRP1 and IRP2) posttranscriptionally regulate expression of several iron metabolism proteins including ferritin and transferrin receptor. Genetically engineered mice that lack IRP2, but have the normal complement of IRP1, develop adult-onset neurodegenerative disease associated with inappropriately high expression of ferritin in degenerating neurons. Here, we report that mice that are homozygous for a targeted deletion of IRP2 and heterozygous for a targeted deletion of IRP1 (IRP1+/- IRP2-/-) develop a much more severe form of neurodegeneration, characterized by widespread axonopathy and eventually by subtle vacuolization in several areas, particularly in the substantia nigra. Axonopathy develops in white matter tracts in which marked increases in ferric iron and ferritin expression are detected. Axonal degeneration is significant and widespread before evidence for abnormalities or loss of neuronal cell bodies can be detected. Ultimately, neuronal cell bodies degenerate in the substantia nigra and some other vulnerable areas, microglia are activated, and vacuoles appear. Mice manifest gait and motor impairment at stages when axonopathy is pronounced, but neuronal cell body loss is minimal. These observations suggest that therapeutic strategies that aim to revitalize neurons by treatment with neurotrophic factors may be of value in IRP2-/- and IRP1+/- IRP2-/- mouse models of neurodegeneration.