Non-Anticoagulant Heparins Are Hepcidin Antagonists for the Treatment of Anemia

Abstract

The peptide hormone hepcidin is a key controller of systemic iron homeostasis, and its expression in the liver is mainly regulated by bone morphogenetic proteins (BMPs), which are heparin binding proteins. In fact, heparins are strong suppressors of hepcidin expression in hepatic cell lines that act by inhibiting the phosphorylation of SMAD1/5/8 proteins elicited by the BMPs. The inhibitory effect of heparins has been demonstrated in cells and in mice, where subcutaneous injections of non-anticoagulant heparins inhibited liver hepcidin expression and increased iron bioavailability. The chemical characteristics for high anti-hepcidin activity in vitro and in vivo include the 2O-and 6O-sulfation and a molecular weight above 7 kDa. The most potent heparins have been found to be the super-sulfated ones, active in hepcidin suppression with a molecular weight as low as 4 kDa. Moreover, the alteration of endogenous heparan sulfates has been found to cause a reduction in hepcidin expression in vitro and in vivo, indicating that heparins act by interfering with the interaction between BMPs and components of the complex involved in the activation of the BMP/SMAD1/5/8 pathway. This review summarizes recent findings on the anti-hepcidin activity of heparins and their possible use for the treatment of anemia caused by hepcidin excess, including the anemia of chronic diseases.

Keywords: anemia; heparin; hepcidin; iron homeostasis.

Figure 1

Scheme of the anti-hepcidin activity of heparin. In the physiological pathway, the binding of BMP6 causes the phosphorylation of Type I receptor by Type II receptor, which phosphorylates SMAD1/5/8 that associates with SMAD4, and the complex enters the nucleus to bind to the responsive element on the hepcidin promoter. The anti-hepcidin activity of heparin is thought to act by sequestering BMP6 and interfering with its binding to the receptors.

Figure 2

The heparan sulfates bound to proteoglycans cover cellular membranes and are thought to participate in the binding of BMP6 to the receptors for activation of the SMAD signaling. This is supported by the evidence that alteration of the endogenous heparan sulfate structure by heparanase overexpression strongly reduced BMP6 signaling and hepcidin expression in cells and mice. Exogenous heparins probably interfere with the roles of endogenous heparan sulfates.