Iron Regulator Hepcidin Impairs Macrophage-Dependent Cardiac Repair After Injury
Zlatanova I, Pinto C, Bonnin P, Mathieu JRR, Bakker W, Vilar J, Lemitre M, Vöhringer D, Vaulont S, Peyssonnaux C, Silvestre JS (2019)
Publication Language: English
Publication Type: Journal article
Publication year: 2019
Journal
Book Volume: 139
Pages Range: 1530-1547
Journal Issue: 12
DOI: 10.1161/CIRCULATIONAHA.118.034545
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 following acute myocardial infarction (AMI). METHODS: Cardiac repair was analyzed in mice harboring specific cardiomyocyte or myeloid cell deficiency of hepcidin and challenged with AMI. RESULTS: We found that the expression of hepcidin was elevated after AMI 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. IL-6 increased hepcidin levels in inflammatory macrophages. Hepcidin deficiency enhanced the number of CD45+/CD11b+/F4/80+/CD64+/MHCIILow/CCR2+ inflammatory macrophages and fostered 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 with CRIS profile
Involved external institutions
Lariboisière Hospital / Hôpital Lariboisière
France (FR)
Institut Cochin (INSERM UMR 1016, CNRS UMR 8104)
France (FR)
Paris Cardiovascular Research Center / Paris Centre de Recherche Cardiovasculaire (PARCC) (INSERM UMR 970)
France (FR)
France (FR)
Institut Cochin (INSERM UMR 1016, CNRS UMR 8104)
France (FR)
Paris Cardiovascular Research Center / Paris Centre de Recherche Cardiovasculaire (PARCC) (INSERM UMR 970)
France (FR)
How to cite
APA:
Zlatanova, I., Pinto, C., Bonnin, P., Mathieu, J.R.R., Bakker, W., Vilar, J.,... Silvestre, J.-S. (2019). Iron Regulator Hepcidin Impairs Macrophage-Dependent Cardiac Repair After Injury. Circulation, 139(12), 1530-1547. https://doi.org/10.1161/CIRCULATIONAHA.118.034545
MLA:
Zlatanova, Ivana, et al. "Iron Regulator Hepcidin Impairs Macrophage-Dependent Cardiac Repair After Injury." Circulation 139.12 (2019): 1530-1547.
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