The role of heparin, heparanase and heparan sulfates in hepcidin regulation

Asperti, Michela; Denardo, Andrea; Gryzik, Magdalena; Arosio, Paolo; Poli, Maura

doi:10.1016/bs.vh.2019.01.008

Cited by 11 publications

(10 citation statements)

References 134 publications

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“…22,23 Preservation of vascular integrity via inhibition of endothelial cell heparinase or impairment of hepcidin formation and concomitant reduction of hyperferritinaemia might be other potential mechanisms by which LMWH exerts its beneficial effects. 24,25 Importantly, we observed curtailed SARS-CoV-2 viral persistence upon qPCR in patients treated with LMWH, when compared to patients without anticoagulation or those using NOAC. These data provide exploratory clinical evidence compatible with a direct effect of LMWH on virus pathology, which was previously suggested in in vitro studies, where heparin was found to interfere with SARS-CoV-2 binding on ACE2 expressing cells, thereby limiting its infectivity.…”

Section: Discussionmentioning

confidence: 76%

Low-molecular-weight heparin use in coronavirus disease 2019 is associated with curtailed viral persistence: a retrospective multicentre observational study

Pereyra

Heber

Schrottmaier

et al. 2021

Cardiovascular Research

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Aim Anticoagulation was associated with improved survival of hospitalized COVID-19 patients in large-scale studies. Yet, the development of COVID-19 associated coagulopathy (CAC) and the mechanism responsible for improved survival of anticoagulated patients with COVID-19 remain largely elusive. This investigation aimed to explore the effects of anticoagulation and low molecular weight heparin (LMWH) in particular on patient outcome, CAC development, thromboinflammation, cell death, and viral persistence. Methods and Results Data of 586 hospitalized COVID-19 patients from three different regions of Austria were evaluated retrospectively. Of these 419 (71.5%) patients received LMWH and 62 (10.5%) received non-vitamin-K antagonist oral anticoagulants (NOAC) during hospitalization. Plasma was collected at different time points in a subset of 106 patients in order to evaluate markers of thromboinflammation (H3Cit-DNA) and the cell death marker cell-free DNA (cfDNA). Use of LMWH was associated with improved survival upon multivariable Cox-regression (hazard ratio = 0.561, 95% confidence interval: 0.348-0.906). Interestingly, neither LMWH nor NOAC was associated with attenuation of D-dimer increase over time, or thromboinflammation. In contrast, anticoagulation was associated with a decrease in cfDNA during hospitalization and curtailed viral persistence was observed in patients using LMWH leading to a four-day reduction of virus positivity upon quantitative polymerase chain reaction (13 [interquartile range: 6-24] versus 9 [interquartile range: 5-16] days, p = 0.009). Conclusions Time courses of hemostatic and thromboinflammatory biomarkers were similar in patients with and without LMWH, indicating either no effects of LMWH on hemostasis or that LMWH reduced hypercoagulability to levels of patients without LMWH. Nonetheless, anticoagulation with LMWH was associated with reduced mortality, improved markers of cell death, and curtailed viral persistence, indicating potential beneficial effects of LMWH beyond hemostasis, which encourages use of LMWH in COVID-19 patients without contraindications. Translational Perspective The data gathered in this retrospective multicenter observational study could confirm an association of improved survival and anticoagulation and could link LMWH use to improved biomarkers of cell death and curtailed persistence of SARS-CoV-2. This encourages the use of this drug in patients without known contraindications in case this effect can be consolidated in randomized controlled trials. Currently performed prospective trials using LMWH in COVID-19 should focus on viral persistence in order to explore an additional field of application for LMWH during this pandemic.

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Section: Discussionmentioning

confidence: 76%

Low-molecular-weight heparin use in coronavirus disease 2019 is associated with curtailed viral persistence: a retrospective multicentre observational study

Pereyra

Heber

Schrottmaier

et al. 2021

Cardiovascular Research

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“…For experiments with TM tissue, human and bovine anterior segment samples were infused, or cultured with replication-defective adenovirus expressing bioactive TGF-β2 (AdhuTGF-β2) or vector (AdEmpty). 25 – 27 Ferric ammonium citrate (FAC) was used as a positive control to trigger hepcidin upregulation, 12 heparin as a hepcidin antagonist, 28 – 30 and N-acetyl-L-Carnosine 31 as an antioxidant in different experimental paradigms.…”

Section: Methodsmentioning

confidence: 99%

TGFβ2-Hepcidin Feed-Forward Loop in the Trabecular Meshwork Implicates Iron in Glaucomatous Pathology

Ashok

Chaudhary

Kritikos

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Elevated levels of transforming-growth-factor (TGF)-β2 in the trabecular meshwork (TM) and aqueous humor are associated with primary open-angle glaucoma (POAG). The underlying mechanism includes alteration of extracellular matrix homeostasis through Smad-dependent and independent signaling. Smad4, an essential co-Smad, upregulates hepcidin, the master regulator of iron homeostasis. Here, we explored whether TGF-β2 upregulates hepcidin, implicating iron in the pathogenesis of POAG. METHODS. Primary human TM cells and human and bovine ex vivo anterior segment organ cultures were exposed to bioactive TGF-β2, hepcidin, heparin (a hepcidin antagonist), or N-acetyl carnosine (an antioxidant), and the change in the expression of hepcidin, ferroportin, ferritin, and TGF-β2 was evaluated by semiquantitative RT-PCR, Western blotting, and immunohistochemistry. Increase in reactive oxygen species (ROS) was quantified with dihydroethidium, an ROS-sensitive dye. RESULTS. Primary human TM cells and bovine TM tissue synthesize hepcidin locally, which is upregulated by bioactive TGF-β2. Hepcidin downregulates ferroportin, its downstream target, increasing ferritin and iron-catalyzed ROS. This causes reciprocal upregulation of TGF-β2 at the transcriptional and translational levels. Heparin downregulates hepcidin, and reduces TGF-β2-mediated increase in ferritin and ROS. Notably, both heparin and N-acetyl carnosine reduce TGF-β2-mediated reciprocal upregulation of TGF-β2. CONCLUSIONS. The above observations suggest that TGF-β2 and hepcidin form a selfsustained feed-forward loop through iron-catalyzed ROS. This loop is partially disrupted by a hepcidin antagonist and an anti-oxidant, implicating iron and ROS in TGF-β2mediated POAG. We propose that modification of currently available hepcidin antagonists for ocular use may prove beneficial for the therapeutic management of TGF-β2-associated POAG.

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“…Peptides corresponding to the C-terminal sequence of BMP-5 or the N-terminal sequence of BMP-2 or BMP-4 were able to stimulate chondrogenesis, perhaps by dislodging HS-immobilized BMPs at the cell surface or in the matrix (Billings et al, 2018). For BMP-6, cooperative binding with contributions from basic amino acid residues in both the N-terminal and C-terminal unstructured tails has been proposed based on site direct mutation studies supported by molecular dynamics calculations; BMP-6 is a hepcidin inducer, so modulation of its activity by heparin/HS may influence iron availability (Asperti et al, 2019;Denardo et al, 2021).…”

Section: Update On the Pharmacology Of Heparin And Related Drugsmentioning

confidence: 99%