Ivana Zlatanova1, Cristina Pinto1, Philippe Bonnin2, Jacques R R Mathieu3, Wineke Bakker1, Jose Vilar1, Mathilde Lemitre1, David Voehringer4, Sophie Vaulont3, Carole Peyssonnaux3, Jean-Sébastien Silvestre1. 1. Institut National de la Santé et de la Recherche Médicale, UMRS-970, Paris Centre de Recherche Cardiovasculaire, Université Paris Descartes, Sorbonne Paris Cité, France (I.Z., C.P., W.B., J.V., M.L., J.-S-.S.). 2. Institut National de la Santé et de la Recherche Médicale, Unit 965, Départment de physiologie Clinique, Assistance Publique Hôpitaux de Paris, Hôpital Lariboisière, France (P.B.). 3. Institut National de la Santé et de la Recherche Médicale U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, France (J.R.R.M., S.V., C.P.). 4. University Hospital Erlangen, Wasserturmstrasse 3/5, Germany (D.V.).
Abstract
BACKGROUND: Defective systemic and local iron metabolism correlates with cardiac disorders. Hepcidin, a master iron sensor, actively tunes iron trafficking. We hypothesized that hepcidin could play a key role to locally regulate cardiac homeostasis after acute myocardial infarction. METHODS: Cardiac repair was analyzed in mice harboring specific cardiomyocyte or myeloid cell deficiency of hepcidin and challenged with acute myocardial infarction. RESULTS: We found that the expression of hepcidin was elevated after acute myocardial infarction and the specific deletion of hepcidin in cardiomyocytes failed to improve cardiac repair and function. However, transplantation of bone marrow-derived cells from hepcidin-deficient mice ( Hamp-/-) or from mice with specific deletion of hepcidin in myeloid cells (LysMCRE/+/ Hampf/f) improved cardiac function. This effect was associated with a robust reduction in the infarct size and tissue fibrosis in addition to favoring cardiomyocyte renewal. Macrophages lacking hepcidin promoted cardiomyocyte proliferation in a prototypic model of apical resection-induced cardiac regeneration in neonatal mice. Interleukin (IL)-6 increased hepcidin levels in inflammatory macrophages. Hepcidin deficiency enhanced the number of CD45+/CD11b+/F4/80+/CD64+/MHCIILow/chemokine (C-C motif) receptor 2 (CCR2)+ inflammatory macrophages and fostered signal transducer and activator of transcription factor-3 (STAT3) phosphorylation, an instrumental step in the release of IL-4 and IL-13. The combined genetic suppression of hepcidin and IL-4/IL-13 in macrophages failed to improve cardiac function in both adult and neonatal injured hearts. CONCLUSIONS: Hepcidin refrains macrophage-induced cardiac repair and regeneration through modulation of IL-4/IL-13 pathways.
BACKGROUND: Defective systemic and local iron metabolism correlates with cardiac disorders. Hepcidin, a master iron sensor, actively tunes iron trafficking. We hypothesized that hepcidin could play a key role to locally regulate cardiac homeostasis after acute myocardial infarction. METHODS: Cardiac repair was analyzed in mice harboring specific cardiomyocyte or myeloid cell deficiency of hepcidin and challenged with acute myocardial infarction. RESULTS: We found that the expression of hepcidin was elevated after acute myocardial infarction and the specific deletion of hepcidin in cardiomyocytes failed to improve cardiac repair and function. However, transplantation of bone marrow-derived cells from hepcidin-deficient mice ( Hamp-/-) or from mice with specific deletion of hepcidin in myeloid cells (LysMCRE/+/ Hampf/f) improved cardiac function. This effect was associated with a robust reduction in the infarct size and tissue fibrosis in addition to favoring cardiomyocyte renewal. Macrophages lacking hepcidin promoted cardiomyocyte proliferation in a prototypic model of apical resection-induced cardiac regeneration in neonatal mice. Interleukin (IL)-6 increased hepcidin levels in inflammatory macrophages. Hepcidin deficiency enhanced the number of CD45+/CD11b+/F4/80+/CD64+/MHCIILow/chemokine (C-C motif) receptor 2 (CCR2)+ inflammatory macrophages and fostered signal transducer and activator of transcription factor-3 (STAT3) phosphorylation, an instrumental step in the release of IL-4 and IL-13. The combined genetic suppression of hepcidin and IL-4/IL-13 in macrophages failed to improve cardiac function in both adult and neonatal injured hearts. CONCLUSIONS:Hepcidin refrains macrophage-induced cardiac repair and regeneration through modulation of IL-4/IL-13 pathways.
Authors: Florian Sicklinger; Ingmar Sören Meyer; Xue Li; Daniel Radtke; Severin Dicks; Moritz P Kornadt; Christina Mertens; Julia K Meier; Kory J Lavine; Yunhang Zhang; Tim Christian Kuhn; Tobias Terzer; Jyoti Patel; Melanie Boerries; Gabriele Schramm; Norbert Frey; Hugo A Katus; David Voehringer; Florian Leuschner Journal: J Clin Invest Date: 2021-07-01 Impact factor: 14.808
Authors: Amy Larson; Towia A Libermann; Heather Bowditch; Gaurav Das; Nikolaos Diakos; Gordon S Huggins; Hassan Rastegar; Frederick Y Chen; Ethan J Rowin; Martin S Maron; Michael T Chin Journal: Int J Mol Sci Date: 2021-03-01 Impact factor: 5.923