title: Oversulfated heparins with low anticoagulant activity are strong and fast inhibitors of hepcidin expression in vitro and in vivo.
abstract: Hepcidin is a peptide hormone that controls systemic iron availability and is upregulated by iron and inflammation. Heparins have been shown to be efficient hepcidin inhibitors both in vitro and in vivo, even when their anticoagulant activity has been abolished by chemical reactions of oxidation/reduction (glycol-split). We analyzed a modified heparin type, characterized by a high, almost saturated, sulfation degree and low molecular weight. It inhibited hepcidin expression in hepatic HepG2 cells, and when used in mice, it readily suppressed liver hepcidin mRNA and serum hepcidin, with a significant decrease of spleen iron. This occurred also in inflammation-model, LPS-treated animals, and after heparin chronic 10-day treatments. The heparin had low/absent anticoagulant activity, as tested for factor-Xa and -IIA, APTT and anti Xa. It reduced triglyceride levels in the mice. This heparin acts faster and is more potent than the glycol split-heparins, probably because of its smaller molecular weight and higher sulfation degree. This modified heparin has potential applications for the treatment of diseases with high hepcidin levels.
authors.affiliation: Molecular Biology laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Poli
authors.affiliation: Molecular Biology laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Asperti
authors.affiliation: Molecular Biology laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ruzzenenti
authors.affiliation: G. Ronzoni Institute for Chemical and Biochemical Research, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Mandelli
authors.affiliation: Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Natascia
authors.initials: N
authors.lastname: Campostrini
authors.affiliation: Laboratorio Analisi Chimico-Cliniche, AO Spedali Civili of Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Martini
authors.affiliation: Molecular Biology laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Di Somma
authors.affiliation: Molecular Biology laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Maccarinelli
authors.affiliation: Department of Medicine, University of Verona, Verona, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Girelli
authors.affiliation: G. Ronzoni Institute for Chemical and Biochemical Research, Milano, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Naggi
authors.affiliation: Molecular Biology laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. Electronic address: paolo.arosio@unibs.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology*; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors / Q000494:pharmacology; D056945:Hep G2 Cells / Q000187:drug effects; D006493:Heparin / Q000737:chemistry* / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry / Q000494:pharmacology; D064451:Hepcidins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011516:Prothrombin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000737:chemistry; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D064451:Hepcidins; D013431:Sulfates; D014280:Triglycerides; D011516:Prothrombin; C025337:Factor IIa; D006493:Heparin; D015951:Factor Xa
keywords: Anemia of chronic diseases; Hepcidin; Iron absorption and metabolism; Low-molecular-weight heparins