title: Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo.
abstract: Hepcidin controls systemic iron availability, and its excess contributes to the anemia of chronic diseases, the most prevalent anemia in hospitalized patients. We previously reported that heparins are efficient hepcidin inhibitors both in vitro and in vivo, but their anticoagulant activity limits therapeutic use. We studied nonanticoagulant heparins produced by N-acetylation and oxidation/reduction (glycol-split) that lost antithrombin-binding affinity. Four nonanticoagulant heparins inhibited hepcidin expression in hepatic HepG2 cells and primary hepatocytes. The 2 most potent ones used in mice suppressed liver hepcidin expression and serum hepcidin in 6 hours, with a significant decrease of spleen iron. This occurred also in lipopolysaccharide (LPS)-treated animals that mimic inflammation, as well as after chronic 1-week treatments, without evident adverse effects on coagulation. Heparin injections increased iron mobilization and facilitated the recovery from the anemia induced by heat-killed Brucella abortus, a model of inflammatory anemia. The heparins were used also in Bmp6(-/-) mice. A single dose of heparin reduced the already low level of hepcidin of these mice and prevented its induction by LPS. These nonanticoagulant compounds impair bone morphogenetic protein /sons of mothers against decapentaplegic signaling with no evident adverse effect in vivo, even when administered chronically. They may offer a strategy for the treatment of diseases with high hepcidin levels.
authors.affiliation: Molecular Biology laboratory, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy;
authors.forename: Maura
authors.initials: M
authors.lastname: Poli
authors.forename: Michela
authors.initials: M
authors.lastname: Asperti
authors.forename: Annamaria
authors.initials: A
authors.lastname: Naggi
authors.forename: Natascia
authors.initials: N
authors.lastname: Campostrini
authors.forename: Domenico
authors.initials: D
authors.lastname: Girelli
authors.forename: Michela
authors.initials: M
authors.lastname: Corbella
authors.forename: Marina
authors.initials: M
authors.lastname: Benzi
authors.forename: Celine
authors.initials: C
authors.lastname: Besson-Fournier
authors.forename: Helene
authors.initials: H
authors.lastname: Coppin
authors.forename: Federica
authors.initials: F
authors.lastname: Maccarinelli
authors.forename: Dario
authors.initials: D
authors.lastname: Finazzi
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
mesh_terms: D000740:Anemia / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics; D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003871:Dermatan Sulfate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006493:Heparin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D064451:Hepcidins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D007501:Iron / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D055418:Bone Morphogenetic Protein 6; C579599:Hamp protein, mouse; D064451:Hepcidins; D018836:Inflammation Mediators; D051798:Inhibitor of Differentiation Protein 1; D008070:Lipopolysaccharides; C504902:RO-heparin; D003871:Dermatan Sulfate; D006493:Heparin; D007501:Iron