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: Maura Poli, Michela Asperti, Annamaria Naggi, Natascia Campostrini, Domenico Girelli, Michela Corbella, Marina Benzi, Celine Besson-Fournier, Helene Coppin, Federica Maccarinelli, Dario Finazzi, Paolo Arosio
• Journal: Blood (Blood) Vol. 123 Issue 10 Pg. 1564-73 (Mar 06 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24398330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bone Morphogenetic Protein 6
• Hamp protein, mouse
• Hepcidins
• Inflammation Mediators
• Inhibitor of Differentiation Protein 1
• Lipopolysaccharides
• RO-heparin
• Dermatan Sulfate
• Heparin
• Iron

Topics

• Anemia (chemically induced, drug therapy, genetics)
• Animals
• Bone Morphogenetic Protein 6 (genetics, metabolism)
• Cell Line
• Dermatan Sulfate (pharmacology)
• Dose-Response Relationship, Drug
• Female
• Gene Expression Regulation (drug effects)
• Hep G2 Cells
• Heparin (administration & dosage, analogs & derivatives, pharmacology)
• Hepcidins (genetics, metabolism)
• Humans
• Inflammation (immunology, metabolism)
• Inflammation Mediators (metabolism)
• Inhibitor of Differentiation Protein 1 (genetics)
• Iron (metabolism)
• Lipopolysaccharides (immunology)
• Mice
• Mice, Knockout
• Promoter Regions, Genetic
• Spleen (drug effects, metabolism)
• Time Factors
• Transcriptional Activation (drug effects)