Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo

Abstract

Key Points• Chemically modified nonanticoagulant heparins are strong inhibitors of hepcidin expression in normal and Bmp6 2/2 mice. • These heparins abolish hepcidin induction caused by LPS, a model of inflammation, and are candidates for treatment of inflammatory anemia.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 antithrombinbinding 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 2/2 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. (Blood. 2014;123(10):1564-1573

BuMPing iron with modified heparins

“…1 Consistent with prior data, the median JAK2 mutant allele burden was higher in ET patients who progressed to PV, as well as in post-PV/ET MF compared with the initial MPN. 1 These data reinforce that PV and JAK2-mutated ET form a continuum wherein phenotype and natural history are substantially influenced by JAK2 allele burden. While investigators decipher how CALR mutations contribute to MPN pathogenesis, it is clear that CALR will be quickly assimilated into World Health Organization diagnostic criteria for ET and PMF.…”

“…Although ET patients carrying a CALR mutation exhibited a better overall survival than PV patients, a nonsignificant trend 1 or no difference in survival 2 was found between CALR and JAK2-mutated ET patients. In contrast, a significant difference (P 5 .04) was observed in 10-year overall survival between these ET subgroups by Klampfl et al 4 The 15-year cumulative incidence of secondary myelofibrosis was similar between CALR-and JAK2-mutated ET and PV, 1 but evolution to leukemia was lower for CALR-mutated ET patients compared with the other groups.…”

“…cumulative thrombosis incidence of 10.5% vs 25.1% identified by Rumi et al 1 The higher thrombosis rate in JAK2-mutated ET patients may be partly attributable to the hyperviscosity associated with higher hematocrit and leukocyte levels, the latter being a putative risk factor for thrombosis in MPNs. Evaluation of leukocyte and platelet activation, as well as hypercoagulability profiles, will lend further insight into this differential propensity for thrombosis.…”

Icariin regulates systemic iron metabolism by increasing hepatic hepcidin expression through Stat3 and Smad1/5/8 signaling

“…through an inflammatory mechanism (34)(35)(36). Exposure to LPS significantly increased hepatic hepcidin expression and there were corresponding alterations in body iron status (data not shown).…”

Hepcidin as a Major Component of Renal Antibacterial Defenses against Uropathogenic Escherichia coli

“…19,24 Interestingly, recent studies from Arosio's group have shown that heparin, acting through SMAD signaling alteration, is a potent inhibitor of hepatic hepcidin. 40,41 This mechanism process may explain the inhibition of hepcidin in CFT073-infected kidney because UPEC may express heparin-like molecules at their cell envelope, as observed in the urinary tract-infective E. coli O10:K5:H4 and O4:K12:H-. 42,43 Further studies are in progress to investigate this mechanism in our UTI model.…”