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Heparin, Heparan Sulfate and Heparanase in Health and Disease
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Heparin, Heparan Sulfate and Heparanase in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (20 December 2023) | Viewed by 13975

Special Issue Editor

Prof. Dr. Nobuaki Higashi

E-Mail Website
Guest Editor
Department of Biochemistry, Hoshi University School of Pharmacy, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan
Interests: allergy; cancer metastasis; fibrosis; infectious diseases; inflammation; cytokines/chemokines; extracellular matrix; glycosaminoglycans; heparan sulfate; heparanase; heparin; inbibitor development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Heparin has been used in many different types of medical and therapeutic applications, including prevention of recent COVID-19 infection-associated symptoms. The anticoagulant action of heparin has been described best. In addition, heparin and a related carbohydrate heparan sulfate can interact and potentially regulate hundreds of functional proteins, including growth factors, cytokines/chemokines, enzymes, danger-associated molecular patterns, extracellular matrix proteins, cell surface proteins, viral proteins etc., as non-anticoagulant actions. It is known that the pentasaccharide sequence in heparin specifically interacts with antithrombin III; however, diversified anionic patterns inside heparin and heparan sulfate possibly include other sulfated sugar sequences (sulfation codes) relevant for interaction with other functional proteins. 

Changes in the nature of anionic carbohydrates, i.e., size, electrostatic potential, and location (soluble or membrane/matrix-bound), greatly influence the functions of associated proteins and the downstream biological events. Furthermore, it has been demonstrated that the cleaved carbohydrate fragments possibly transduce inflammatory signals. Such postsynthetic changes can be achieved by the action of carbohydrate-editing enzymes such as heparanase and sulfatases. Heparanase, an endoglycosidase of heparin/heparan sulfate, cleaves the carbohydrates and thereby influences a vast field of biological events, such as cancer malignancy, angiogenesis, inflammation, fibrosis, viral infection, etc.

To combine the subjects together, the Special Issue focuses on underlying molecular mechanisms that explain molecular, biological, pathological, and therapeutic actions of heparin, heparan sulfate, and heparanase, also focusing on the development of heparanase inhibitors as well as other analytical tools to investigate carbohydrates. Original research and review papers are welcomed.

Prof. Dr. Nobuaki Higashi
Guest Editor

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Keywords

  • allergy
  • angiogenesis
  • cellular trafficking
  • cancer metastasis
  • cardiovascular diseases
  • exosome/extracellular vesicles
  • fibrosis
  • glycocalyx
  • glycosaminoglycans
  • heparan sulfate
  • heparanase
  • heparin
  • immune responses
  • inflammation
  • inhibitor development
  • sepsis/SIRS (systemic inflammatory response syndrome)
  • sulfatase
  • viral infections

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Published Papers (6 papers)

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Research

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14 pages, 1127 KiB  
Article
The Uptake of Heparanase into Mast Cells Is Regulated by Its Enzymatic Activity to Degrade Heparan Sulfate
by Jia Shi, Yoshiki Onuki, Fumiya Kawanami, Naoko Miyagawa, Fumika Iwasaki, Haruna Tsuda, Katsuhiko Takahashi, Teruaki Oku, Masato Suzuki, Kyohei Higashi, Hayamitsu Adachi, Yoshio Nishimura, Motowo Nakajima, Tatsuro Irimura and Nobuaki Higashi
Int. J. Mol. Sci. 2024, 25(11), 6281; https://doi.org/10.3390/ijms25116281 - 6 Jun 2024
Viewed by 1382
Abstract
Mast cells take up extracellular latent heparanase and store it in secretory granules. The present study examined whether the enzymatic activity of heparanase regulates its uptake efficiency. Recombinant mouse heparanase mimicking both the latent and mature forms (L-Hpse and M-Hpse, respectively) was internalized [...] Read more.
Mast cells take up extracellular latent heparanase and store it in secretory granules. The present study examined whether the enzymatic activity of heparanase regulates its uptake efficiency. Recombinant mouse heparanase mimicking both the latent and mature forms (L-Hpse and M-Hpse, respectively) was internalized into mastocytoma MST cells, peritoneal cell-derived mast cells, and bone marrow-derived mast cells. The internalized amount of L-Hpse was significantly higher than that of M-Hpse. In MST cells, L-Hpse was continuously internalized for up to 8 h, while the uptake of M-Hpse was saturated after 2 h of incubation. L-Hpse and M-Hpse are similarly bound to the MST cell surface. The expression level of cell surface heparan sulfate was reduced in MST cells incubated with M-Hpse. The internalized amount of M-Hpse into mast cells was significantly increased in the presence of heparastatin (SF4), a small molecule heparanase inhibitor that does not affect the binding of heparanase to immobilized heparin. Enzymatically quiescent M-Hpse was prepared with a point mutation at Glu335. The internalized amount of mutated M-Hpse was significantly higher than that of wild-type M-Hpse but similar to that of wild-type and mutated L-Hpse. These results suggest that the enzymatic activity of heparanase negatively regulates the mast cell-mediated uptake of heparanase, possibly via the downregulation of cell surface heparan sulfate expression. Full article
(This article belongs to the Special Issue Heparin, Heparan Sulfate and Heparanase in Health and Disease)
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22 pages, 6566 KiB  
Article
Dichotomous Effects of Glypican-4 on Cancer Progression and Its Crosstalk with Oncogenes
by Victor Chérouvrier Hansson, Fang Cheng, Grigorios Georgolopoulos and Katrin Mani
Int. J. Mol. Sci. 2024, 25(7), 3945; https://doi.org/10.3390/ijms25073945 - 2 Apr 2024
Cited by 1 | Viewed by 2095
Abstract
Glypicans are linked to various aspects of neoplastic behavior, and their therapeutic value has been proposed in different cancers. Here, we have systematically assessed the impact of GPC4 on cancer progression through functional genomics and transcriptomic analyses across a broad range of cancers. [...] Read more.
Glypicans are linked to various aspects of neoplastic behavior, and their therapeutic value has been proposed in different cancers. Here, we have systematically assessed the impact of GPC4 on cancer progression through functional genomics and transcriptomic analyses across a broad range of cancers. Survival analysis using TCGA cancer patient data reveals divergent effects of GPC4 expression across various cancer types, revealing elevated GPC4 expression levels to be associated with both poor and favorable prognoses in a cancer-dependent manner. Detailed investigation of the role of GPC4 in glioblastoma and non-small cell lung adenocarcinoma by genetic perturbation studies displays opposing effects on these cancers, where the knockout of GPC4 with CRISPR/Cas9 attenuated proliferation of glioblastoma and augmented proliferation of lung adenocarcinoma cells and the overexpression of GPC4 exhibited a significant and opposite effect. Further, the overexpression of GPC4 in GPC4-knocked-down glioblastoma cells restored the proliferation, indicating its mitogenic effect in this cancer type. Additionally, a survival analysis of TCGA patient data substantiated these findings, revealing an association between elevated levels of GPC4 and a poor prognosis in glioblastoma, while indicating a favorable outcome in lung carcinoma patients. Finally, through transcriptomic analysis, we attempted to assign mechanisms of action to GPC4, as we find it implicated in cell cycle control and survival core pathways. The analysis revealed upregulation of oncogenes, including FGF5, TGF-β superfamily members, and ITGA-5 in glioblastoma, which were downregulated in lung adenocarcinoma patients. Our findings illuminate the pleiotropic effect of GPC4 in cancer, underscoring its potential as a putative prognostic biomarker and indicating its therapeutic implications in a cancer type dependent manner. Full article
(This article belongs to the Special Issue Heparin, Heparan Sulfate and Heparanase in Health and Disease)
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12 pages, 5968 KiB  
Article
M6229 Protects against Extracellular-Histone-Induced Liver Injury, Kidney Dysfunction, and Mortality in a Rat Model of Acute Hyperinflammation
by Chris P. M. Reutelingsperger, Marion J. Gijbels, Henri Spronk, Rene Van Oerle, Roy Schrijver, Peter Ekhart, Sjef de Kimpe and Gerry A. F. Nicolaes
Int. J. Mol. Sci. 2024, 25(3), 1376; https://doi.org/10.3390/ijms25031376 - 23 Jan 2024
Cited by 4 | Viewed by 1720
Abstract
Extracellular histones have been shown to act as DAMPs in a variety of inflammatory diseases. Moreover, they have the ability to induce cell death. In this study, we show that M6229, a low-anticoagulant fraction of unfractionated heparin (UFH), rescues rats that were challenged [...] Read more.
Extracellular histones have been shown to act as DAMPs in a variety of inflammatory diseases. Moreover, they have the ability to induce cell death. In this study, we show that M6229, a low-anticoagulant fraction of unfractionated heparin (UFH), rescues rats that were challenged by continuous infusion of calf thymus histones at a rate of 25 mg histones/kg/h. Histone infusion by itself induced hepatic and homeostatic dysfunction characterized by elevated activity of hepatic enzymes (ASAT and ALAT) and serum lactate levels as well as by a renal dysfunction, which contributed to the significantly increased mortality rate. M6229 was able to restore normal levels of both hepatic and renal parameters at 3 and 9 mg M6229/kg/h and prevented mortality of the animals. We conclude that M6229 is a promising therapeutic agent to treat histone-mediated disease. Full article
(This article belongs to the Special Issue Heparin, Heparan Sulfate and Heparanase in Health and Disease)
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29 pages, 5786 KiB  
Article
Block Synthesis and Step-Growth Polymerization of C-6-Sulfonatomethyl-Containing Sulfated Malto-Oligosaccharides and Their Biological Profiling
by Mihály Herczeg, Fruzsina Demeter, Tibor Nagy, Ágnes Rusznyák, Jan Hodek, Éva Sipos, István Lekli, Ferenc Fenyvesi, Jan Weber, Sándor Kéki and Anikó Borbás
Int. J. Mol. Sci. 2024, 25(1), 677; https://doi.org/10.3390/ijms25010677 - 4 Jan 2024
Viewed by 2032
Abstract
Highly sulfated malto-oligomers, similar to heparin and heparan-sulfate, have good antiviral, antimetastatic, anti-inflammatory and cell growth inhibitory effects. Due to their broad biological activities and simple structure, sulfated malto-oligomer derivatives have a great therapeutic potential, therefore, the development of efficient synthesis methods for [...] Read more.
Highly sulfated malto-oligomers, similar to heparin and heparan-sulfate, have good antiviral, antimetastatic, anti-inflammatory and cell growth inhibitory effects. Due to their broad biological activities and simple structure, sulfated malto-oligomer derivatives have a great therapeutic potential, therefore, the development of efficient synthesis methods for their production is of utmost importance. In this work, preparation of α-(1→4)-linked oligoglucosides containing a sulfonatomethyl moiety at position C-6 of each glucose unit was studied by different approaches. Malto-oligomeric sulfonic acid derivatives up to dodecasaccharides were prepared by polymerization using different protecting groups, and the composition of the product mixtures was analyzed by MALDI-MS methods and size-exclusion chromatography. Synthesis of lower oligomers was also accomplished by stepwise and block synthetic methods, and then the oligosaccharide products were persulfated. The antiviral, anti-inflammatory and cell growth inhibitory activity of the fully sulfated malto-oligosaccharide sulfonic acids were determined by in vitro tests. Four tested di- and trisaccharide sulfonic acids effectively inhibited the activation of the TNF-α-mediated inflammatory pathway without showing cytotoxicity. Full article
(This article belongs to the Special Issue Heparin, Heparan Sulfate and Heparanase in Health and Disease)
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11 pages, 1532 KiB  
Article
Zn2+ Differentially Influences the Neutralisation of Heparins by HRG, Fibrinogen, and Fibronectin
by Amélie I. S. Sobczak, Ramzi A. Ajjan and Alan J. Stewart
Int. J. Mol. Sci. 2023, 24(23), 16667; https://doi.org/10.3390/ijms242316667 - 23 Nov 2023
Viewed by 1187
Abstract
For coagulation to be initiated, anticoagulant glycosaminoglycans (GAGs) such as heparins need to be neutralised to allow fibrin clot formation. Platelet activation triggers the release of several proteins that bind GAGs, including histidine-rich glycoprotein (HRG), fibrinogen, and fibronectin. Zn2+ ions are also [...] Read more.
For coagulation to be initiated, anticoagulant glycosaminoglycans (GAGs) such as heparins need to be neutralised to allow fibrin clot formation. Platelet activation triggers the release of several proteins that bind GAGs, including histidine-rich glycoprotein (HRG), fibrinogen, and fibronectin. Zn2+ ions are also released and have been shown to enhance the binding of HRG to heparins of a high molecular weight (HMWH) but not to those of low molecular weight (LMWH). The effect of Zn2+ on fibrinogen and fibronectin binding to GAGs is unknown. Here, chromogenic assays were used to measure the anti-factor Xa and anti-thrombin activities of heparins of different molecular weights and to assess the effects of HRG, fibrinogen, fibronectin, and Zn2+. Surface plasmon resonance was also used to examine the influence of Zn2+ on the binding of fibrinogen to heparins of different molecular weights. Zn2+ had no effect on the neutralisation of anti-factor Xa (FXa) or anti-thrombin activities of heparin by fibronectin, whereas it enhanced the neutralisation of unfractionated heparin (UFH) and HMWH by both fibrinogen and HRG. Zn2+ also increased neutralisation of the anti-FXa activity of LMWH by fibrinogen but not HRG. SPR showed that Zn2+ increased fibrinogen binding to both UFH and LMWH in a concentration-dependent manner. The presented results reveal that an increase in Zn2+ concentration has differential effects upon anticoagulant GAG neutralisation by HRG and fibrinogen, with implications for modulating anti-coagulant activity in plasma. Full article
(This article belongs to the Special Issue Heparin, Heparan Sulfate and Heparanase in Health and Disease)
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Review

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18 pages, 1073 KiB  
Review
Heparan Sulfate and Sialic Acid in Viral Attachment: Two Sides of the Same Coin?
by Ivan Emmanuel Ramos-Martínez, Edgar Ramos-Martínez, René Álvaro Segura-Velázquez, Manuel Saavedra-Montañez, Jacquelynne Brenda Cervantes-Torres, Marco Cerbón, Dulce Papy-Garcia, Edgar Zenteno and José Ivan Sánchez-Betancourt
Int. J. Mol. Sci. 2022, 23(17), 9842; https://doi.org/10.3390/ijms23179842 - 30 Aug 2022
Cited by 14 | Viewed by 4632
Abstract
Sialic acids and heparan sulfates make up the outermost part of the cell membrane and the extracellular matrix. Both structures are characterized by being negatively charged, serving as receptors for various pathogens, and are highly expressed in the respiratory and digestive tracts. Numerous [...] Read more.
Sialic acids and heparan sulfates make up the outermost part of the cell membrane and the extracellular matrix. Both structures are characterized by being negatively charged, serving as receptors for various pathogens, and are highly expressed in the respiratory and digestive tracts. Numerous viruses use heparan sulfates as receptors to infect cells; in this group are HSV, HPV, and SARS-CoV-2. Other viruses require the cell to express sialic acids, as is the case in influenza A viruses and adenoviruses. This review aims to present, in a general way, the participation of glycoconjugates in viral entry, and therapeutic strategies focused on inhibiting the interaction between the virus and the glycoconjugates. Interestingly, there are few studies that suggest the participation of both glycoconjugates in the viruses addressed here. Considering the biological redundancy that exists between heparan sulfates and sialic acids, we propose that it is important to jointly evaluate and design strategies that contemplate inhibiting the interactions of both glycoconjugates. This approach will allow identifying new receptors and lead to a deeper understanding of interspecies transmission. Full article
(This article belongs to the Special Issue Heparin, Heparan Sulfate and Heparanase in Health and Disease)
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