Francesca Vinchi1,2,3,4, Graca Porto5,6,7, Andreas Simmelbauer1,2, Sandro Altamura1,2,4, Sara T Passos3, Maciej Garbowski8, André M N Silva9, Sebastian Spaich10, Svenja E Seide4, Richard Sparla1, Matthias W Hentze2,11, Martina U Muckenthaler1,2,11. 1. Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Otto Meyerhof Zentrum, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany. 2. Iron Homeostasis Group, Molecular Medicine Partnership Unit (MMPU), Heidelberg University, Im Neuenheimer Feld 350, 69120, Heidelberg & European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany. 3. New York Blood Center (NYBC), Iron Research Program, Lindsley F. Kimball Research Institute (LFKRI), 310 East 67th Street, 10065, New York, NY, USA. 4. Institute of Medical Biometry and Informatics (IMBI), University Hospital Heidelberg, Im Neuenheimer Feld 130.3, 69120 Heidelberg, Germany. 5. Centro Hospitalar do Porto-Hospital Santo António, Largo do Prof. Abel Slazar, 4099-001 Porto, Portugal. 6. Instituto de Biologia Molecular e Celular & Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen, 4200-135 Porto, Portugal. 7. Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal. 8. Hematology Department, University College London Cancer Institute, London, aul O'Gorman Bld, 72 Huntley Street, WC1E 6DD, London, UK. 9. Departamento de Quimica e Bioquimica, REQUIMITE-LAQV, Faculdade de Ciencias, University of Porto, Rua Do Campo Alegre, 4169-007 Porto, Portugal. 10. Department of Cardiology, Angiology and Pneumonology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. 11. European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Abstract
AIMS: Whether and how iron affects the progression of atherosclerosis remains highly debated. Here, we investigate susceptibility to atherosclerosis in a mouse model (ApoE-/- FPNwt/C326S), which develops the disease in the context of elevated non-transferrin bound serum iron (NTBI). METHODS AND RESULTS: Compared with normo-ferremic ApoE-/- mice, atherosclerosis is profoundly aggravated in iron-loaded ApoE-/- FPNwt/C326S mice, suggesting a pro-atherogenic role for iron. Iron heavily deposits in the arterial media layer, which correlates with plaque formation, vascular oxidative stress and dysfunction. Atherosclerosis is exacerbated by iron-triggered lipid profile alterations, vascular permeabilization, sustained endothelial activation, elevated pro-atherogenic inflammatory mediators, and reduced nitric oxide availability. NTBI causes iron overload, induces reactive oxygen species production and apoptosis in cultured vascular cells, and stimulates massive MCP-1-mediated monocyte recruitment, well-established mechanisms contributing to atherosclerosis. NTBI-mediated toxicity is prevented by transferrin- or chelator-mediated iron scavenging. Consistently, a low-iron diet and iron chelation therapy strongly improved the course of the disease in ApoE-/- FPNwt/C326S mice. Our results are corroborated by analyses of serum samples of haemochromatosis patients, which show an inverse correlation between the degree of iron depletion and hallmarks of endothelial dysfunction and inflammation. CONCLUSION: Our data demonstrate that NTBI-triggered iron overload aggravates atherosclerosis and unravel a causal link between NTBI and the progression of atherosclerotic lesions. Our findings support clinical applications of iron restriction in iron-loaded individuals to counteract iron-aggravated vascular dysfunction and atherosclerosis. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Whether and how iron affects the progression of atherosclerosis remains highly debated. Here, we investigate susceptibility to atherosclerosis in a mouse model (ApoE-/- FPNwt/C326S), which develops the disease in the context of elevated non-transferrin bound serum iron (NTBI). METHODS AND RESULTS: Compared with normo-ferremic ApoE-/- mice, atherosclerosis is profoundly aggravated in iron-loaded ApoE-/- FPNwt/C326Smice, suggesting a pro-atherogenic role for iron. Iron heavily deposits in the arterial media layer, which correlates with plaque formation, vascular oxidative stress and dysfunction. Atherosclerosis is exacerbated by iron-triggered lipid profile alterations, vascular permeabilization, sustained endothelial activation, elevated pro-atherogenic inflammatory mediators, and reduced nitric oxide availability. NTBI causes iron overload, induces reactive oxygen species production and apoptosis in cultured vascular cells, and stimulates massive MCP-1-mediated monocyte recruitment, well-established mechanisms contributing to atherosclerosis. NTBI-mediated toxicity is prevented by transferrin- or chelator-mediated iron scavenging. Consistently, a low-iron diet and iron chelation therapy strongly improved the course of the disease in ApoE-/- FPNwt/C326Smice. Our results are corroborated by analyses of serum samples of haemochromatosispatients, which show an inverse correlation between the degree of iron depletion and hallmarks of endothelial dysfunction and inflammation. CONCLUSION: Our data demonstrate that NTBI-triggered iron overload aggravates atherosclerosis and unravel a causal link between NTBI and the progression of atherosclerotic lesions. Our findings support clinical applications of iron restriction in iron-loaded individuals to counteract iron-aggravated vascular dysfunction and atherosclerosis. Published on behalf of the European Society of Cardiology. All rights reserved.
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