Is iron deficiency caused by BMPR2 mutations or dysfunction in pulmonary arterial hypertension patients?

Pulmonary Circulation, vol. 13, pp. e12242

Abstract

Abstract Iron deficiency is common in idiopathic and heritable pulmonary arterial hypertension patients (I/HPAH). A previous report suggested a dysregulation of the iron hormone hepcidin, which is controlled by BMP/SMAD signaling involving the bone morphogenetic protein receptor 2 (BMPR‐II). Pathogenic variants in the BMPR2 gene are the most common cause of HPAH. Their effect on patients' hepcidin levels has not been investigated. The aim of this study was to assess whether iron metabolism and regulation of the iron regulatory hormone hepcidin was disturbed in I/HPAH patients with and without a pathogenic variant in the gene BMPR2 compared to healthy controls. In this explorative, cross‐sectional study hepcidin serum levels were quantified by enzyme‐linked immunosorbent assay. We measured iron status, inflammatory parameters and hepcidin modifying proteins such as IL6, erythropoietin, and BMP2, BMP6 in addition to BMPR‐II protein and mRNA levels. Clinical routine parameters were correlated with hepcidin levels. In total 109 I/HPAH patients and controls, separated into three groups, 23 BMPR2 variant‐carriers, 56 BMPR2 noncarriers and 30 healthy controls were enrolled. Of these, 84% had iron deficiency requiring iron supplementation. Hepcidin levels were not different between groups and corresponded to the degree of iron deficiency. The levels of IL6, erythropoietin, BMP2, or BMP6 showed no correlation with hepcidin expression. Hence, iron homeostasis and hepcidin regulation was largely independent from these parameters. I/HPAH patients had a physiologically normal iron regulation and no false elevation of hepcidin levels. Iron deficiency was prevalent albeit independent of pathogenic variants in the BMPR2 gene.

Authors 17

1. Vivienne Theobald

   Heidelberg University · University Hospital Heidelberg · German Center for Lung Research

   Affiliation as printed

   Center for Pulmonary Hypertension Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital Heidelberg Germany

   Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

   Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany

   Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

2. Ekkehard Grünig

   Heidelberg University · University Hospital Heidelberg · German Center for Lung Research

   Affiliation as printed

   Center for Pulmonary Hypertension Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital Heidelberg Germany

   Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

   Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany

   Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

3. Nicola Benjamin

   Heidelberg University · University Hospital Heidelberg · German Center for Lung Research

   Affiliation as printed

   Center for Pulmonary Hypertension Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital Heidelberg Germany

   Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

   Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany

   Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

4. Hans‐Jürgen Seyfarth

   University Hospital Leipzig · Leipzig University

   Affiliation as printed

   Department of Pneumology, Medical Clinic II University Hospital of Leipzig Leipzig Germany

   Department of Pneumology, Medical Clinic II, University Hospital of Leipzig, Leipzig, Germany

5. Michael Halank

   University Hospital Carl Gustav Carus

   Affiliation as printed

   Medical Clinic I University Hospital of Dresden Dresden Germany

   Medical Clinic I, University Hospital of Dresden, Dresden, Germany

6. Marc Andre Schneider

   Heidelberg University · University Hospital Heidelberg · German Center for Lung Research

   Affiliation as printed

   Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

   Translational Research Unit Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital Heidelberg Germany

   Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

   Translational Research Unit, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany

7. Sarah Richtmann

   Heidelberg University · University Hospital Heidelberg · German Center for Lung Research

   Affiliation as printed

   Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

   Translational Research Unit Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital Heidelberg Germany

   Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

   Translational Research Unit, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany

8. Daniel N. Kazdal

   Heidelberg University · University Hospital Heidelberg · German Center for Lung Research

   Affiliation as printed

   Institute of Pathology Heidelberg University Hospital Heidelberg Germany

   Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

   Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany

   Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

9. Katrin Hinderhofer

   Heidelberg University

   Affiliation as printed

   Laboratory for Molecular Diagnostics, Institute of Human Genetics Heidelberg University Heidelberg Germany

   Laboratory for Molecular Diagnostics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

10. Panagiota Xanthouli

    Heidelberg University · University Hospital Heidelberg · German Center for Lung Research

    Affiliation as printed

    Center for Pulmonary Hypertension Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital Heidelberg Germany

    Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

    Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

11. Benjamin Egenlauf

    Heidelberg University · University Hospital Heidelberg · German Center for Lung Research

    Affiliation as printed

    Center for Pulmonary Hypertension Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital Heidelberg Germany

    Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

    Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

12. Satenik Harutyunova

    Heidelberg University · University Hospital Heidelberg · German Center for Lung Research

    Affiliation as printed

    Center for Pulmonary Hypertension Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital Heidelberg Germany

    Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

    Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

13. Marius M. Hoeper

    Medizinische Hochschule Hannover · German Center for Lung Research

    Affiliation as printed

    Department of Pneumology, Hannover Medical School, Biomedical Research in End‐stage and Obstructive Lung Disease Hannover (BREATH) German Center for Lung Research (DZL) Hannover Germany

    Department of Pneumology, Hannover Medical School, Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany

14. Danny David Jonigk Aachen Institute of Pathology

    Medizinische Hochschule Hannover · Universitätsklinikum Aachen · German Center for Lung Research · RWTH Aachen University

    Affiliation as printed

    Hannover Medical School, Institute for Pathology, German Center for Lung Research (DZL) Biomedical Research in End‐stage and Obstructive Lung Disease Hannover (BREATH) Hannover Germany

    Institute of Pathology RWTH Aachen University Hospital Aachen Germany

    Hannover Medical School, Institute for Pathology, German Center for Lung Research (DZL), Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany

    Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany

15. Richard Sparla

    Heidelberg University · University Hospital Heidelberg · German Center for Lung Research

    Affiliation as printed

    Centre for Translational Biomedical Iron Research, Hematology, Immunology and Pulmonology University Hospital Heidelberg Heidelberg Germany

    Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

    Centre for Translational Biomedical Iron Research, Hematology, Immunology and Pulmonology, University Hospital Heidelberg, Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

16. Martina Ulrike Muckenthaler

    Heidelberg University · University Hospital Heidelberg · German Centre for Cardiovascular Research · German Center for Lung Research

    Affiliation as printed

    Centre for Translational Biomedical Iron Research, Hematology, Immunology and Pulmonology University Hospital Heidelberg Heidelberg Germany

    German Centre for Cardiovascular Research (DZHK) Partner Site Heidelberg/Mannheim Heidelberg Germany

    Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

    Centre for Translational Biomedical Iron Research, Hematology, Immunology and Pulmonology, University Hospital Heidelberg, Heidelberg, Germany

    German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

17. Christina A. Eichstaedt corresponding

    Heidelberg University · University Hospital Heidelberg · German Centre for Cardiovascular Research · German Center for Lung Research

    Affiliation as printed

    Center for Pulmonary Hypertension Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital Heidelberg Germany

    German Centre for Cardiovascular Research (DZHK) Partner Site Heidelberg/Mannheim Heidelberg Germany

    Laboratory for Molecular Diagnostics, Institute of Human Genetics Heidelberg University Heidelberg Germany

    Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) Heidelberg Germany

    Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany

    German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Heidelberg, Germany

    Laboratory for Molecular Diagnostics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany