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: Maura Poli, Michela Asperti, Paola Ruzzenenti, Luca Mandelli, Natascia Campostrini, Giuliana Martini, Margherita Di Somma, Federica Maccarinelli, Domenico Girelli, Annamaria Naggi, Paolo Arosio
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 92 Issue 3 Pg. 467-75 (Dec 01 2014) ISSN: 1873-2968 [Electronic] England
• PMID: 25241290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Anticoagulants
• Factor Xa Inhibitors
• Heparin, Low-Molecular-Weight
• Hepcidins
• Sulfates
• Triglycerides
• Prothrombin
• Factor IIa
• Heparin
• Factor Xa

Topics

• Animals
• Anticoagulants (chemistry, pharmacology)
• Factor Xa (metabolism)
• Factor Xa Inhibitors (pharmacology)
• Hep G2 Cells (drug effects)
• Heparin (chemistry, pharmacology)
• Heparin, Low-Molecular-Weight (chemistry, pharmacology)
• Hepcidins (antagonists & inhibitors, metabolism)
• Humans
• Liver (drug effects, metabolism)
• Mice, Inbred C57BL
• Prothrombin (metabolism)
• Structure-Activity Relationship
• Sulfates (chemistry)
• Triglycerides (metabolism)