title: Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo.
abstract: Hepcidin is a major regulator of iron homeostasis, and its expression in liver is regulated by iron, inflammation, and erythropoietic activity with mechanisms that involve bone morphogenetic proteins (BMPs) binding their receptors and coreceptors. Here we show that exogenous heparin strongly inhibited hepcidin expression in hepatic HepG2 cells at pharmacologic concentrations, with a mechanism that probably involves bone morphogenetic protein 6 sequestering and the blocking of SMAD signaling. Treatment of mice with pharmacologic doses of heparin inhibited liver hepcidin mRNA expression and SMAD phosphorylation, reduced spleen iron concentration, and increased serum iron. Moreover, we observed a strong reduction of serum hepcidin in 5 patients treated with heparin to prevent deep vein thrombosis, which was accompanied by an increase of serum iron and a reduction of C-reactive protein levels. The data show an unrecognized role for heparin in regulating iron homeostasis and indicate novel approaches to the treatment of iron-restricted iron deficiency anemia.
authors.affiliation: Dipartimento Materno Infantile e Tecnologie Biomediche, Università di Brescia, Brescia, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Poli
authors.forename: Domenico
authors.initials: D
authors.lastname: Girelli
authors.forename: Natascia
authors.initials: N
authors.lastname: Campostrini
authors.forename: Federica
authors.initials: F
authors.lastname: Maccarinelli
authors.forename: Dario
authors.initials: D
authors.lastname: Finazzi
authors.forename: Sara
authors.initials: S
authors.lastname: Luscieti
authors.forename: Antonella
authors.initials: A
authors.lastname: Nai
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D055418:Bone Morphogenetic Protein 6 / Q000494:pharmacology; D002097:C-Reactive Protein / Q000378:metabolism; D005260:Female; D000077425:Fondaparinux; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006493:Heparin / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D064451:Hepcidins; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007501:Iron / Q000097:blood / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011134:Polysaccharides / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051785:Smad Proteins / Q000378:metabolism*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D020246:Venous Thrombosis / Q000097:blood / Q000188:drug therapy
chemical_list: D000925:Anticoagulants; D023181:Antimicrobial Cationic Peptides; D055418:Bone Morphogenetic Protein 6; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D006495:Heparin, Low-Molecular-Weight; D064451:Hepcidins; D015850:Interleukin-6; D011134:Polysaccharides; D051785:Smad Proteins; C078918:ITF 300; D006493:Heparin; D002097:C-Reactive Protein; D007501:Iron; D000077425:Fondaparinux