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Advances in Heparin, Heparan Sulfate and Heparanase

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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 (31 October 2022) | Viewed by 32059

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Prof. Dr. Nobuaki Higashi

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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
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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 exert non-anticoagulant actions, i.e. they 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. It is known that the pentasaccharide sequence in heparin specifically interacts with antithrombin III, however it is still challenging to understand how diversified anionic patterns inside heparin and heparan sulfate interact with other functional proteins.

Changes in the nature of the anionic carbohydrates, i.e., size, electrostatic potential and location (soluble or membrane/matrix-bound), greatly influence the protein functions and the following biological events. Furthermore, it has been demonstrated that the cleaved carbohydrate fragments can solely transduce inflammatory signals. Such postsynthetic changes can be achieved by the action of 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, this Special Issue will include papers investigating the underlying molecular mechanisms that explain biological, pathological, and therapeutic actions of heparin, heparan sulfate and heparanase, development of heparanase inhibitors, etc. Original research and review papers are welcome.

Prof. Dr. Nobuaki Higashi
Guest Editor

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Keywords

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

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Advances in Heparin, Heparan Sulfate and Heparanase, 2nd Edition in International Journal of Molecular Sciences

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16 pages, 3708 KiB

Open AccessArticle

The Role of Heparan Sulfate in CCL26-Induced Eosinophil Chemotaxis

by Alexandra Pum, Maria Ennemoser, Tanja Gerlza and Andreas J. Kungl

Int. J. Mol. Sci. 2022, 23(12), 6519; https://doi.org/10.3390/ijms23126519 - 10 Jun 2022

Cited by 4 | Viewed by 1721

Abstract

Proinflammatory chemokine ligand 26 (CCL26, eotaxin-3) mediates transendothelial cell migration of eosinophils by binding and activating the G-protein-coupled (GPC) chemokine receptor 3 on the surface of eosinophilic cells. Here we have investigated the role of glycosaminoglycans (GAGs) as potential co-receptors in the process of CCL26-induced eosinophil chemotaxis. For this purpose, we have first identified the GAG-binding site of CCL26 by a site-directed mutagenesis approach in the form of an alanine screening. A panel of GAG-binding-deficient mutants has been designed, generated, and analyzed with respect to their binding affinities to heparan sulphate (HS) by isothermal fluorescence titration studies. This showed that basic amino acids in the α-helical part of CCL26 are strongly involved in GAG-binding. In chemotaxis experiments, we found that decreased GAG-binding affinity correlated with decreased chemotactic activity, which indicates an involvement of GAGs in eosinophil migration. This was further proven by the negative impact of heparinase III treatment and, independently, by the incubation of eosinophils with an anti heparan sulfate antibody. We finally investigated eosinophils’ proteoglycan (PG) expression patterns by real-time PCR, which revealed the highest expression level for serglycin. Including an anti-serglycin antibody in CCL26-induced eosinophil migration experiments reduced the chemotaxis of these immune cells, thereby proving the dependence of eosinophil mobilization on the proteoglycan serglycin. Full article

(This article belongs to the Special Issue Advances in Heparin, Heparan Sulfate and Heparanase)

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19 pages, 4195 KiB

Open AccessArticle

Sulfated Hyaluronan Binds to Heparanase and Blocks Its Enzymatic and Cellular Actions in Carcinoma Cells

by Jia Shi, Riku Kanoya, Yurina Tani, Sodai Ishikawa, Rino Maeda, Sana Suzuki, Fumiya Kawanami, Naoko Miyagawa, Katsuhiko Takahashi, Teruaki Oku, Ami Yamamoto, Kaori Fukuzawa, Motowo Nakajima, Tatsuro Irimura and Nobuaki Higashi

Int. J. Mol. Sci. 2022, 23(9), 5055; https://doi.org/10.3390/ijms23095055 - 2 May 2022

Cited by 5 | Viewed by 2730

Abstract

We examined whether sulfated hyaluronan exerts inhibitory effects on enzymatic and biological actions of heparanase, a sole endo-beta-glucuronidase implicated in cancer malignancy and inflammation. Degradation of heparan sulfate by human and mouse heparanase was inhibited by sulfated hyaluronan. In particular, high-sulfated hyaluronan modified with approximately 2.5 sulfate groups per disaccharide unit effectively inhibited the enzymatic activity at a lower concentration than heparin. Human and mouse heparanase bound to immobilized sulfated hyaluronan. Invasion of heparanase-positive colon-26 cells and 4T1 cells under 3D culture conditions was significantly suppressed in the presence of high-sulfated hyaluronan. Heparanase-induced release of CCL2 from colon-26 cells was suppressed in the presence of sulfated hyaluronan via blocking of cell surface binding and subsequent intracellular NF-κB-dependent signaling. The inhibitory effect of sulfated hyaluronan is likely due to competitive binding to the heparanase molecule, which antagonizes the heparanase-substrate interaction. Fragment molecular orbital calculation revealed a strong binding of sulfated hyaluronan tetrasaccharide to the heparanase molecule based on electrostatic interactions, particularly characterized by interactions of (−1)- and (−2)-positioned sulfated sugar residues with basic amino acid residues composing the heparin-binding domain-1 of heparanase. These results propose a relevance for sulfated hyaluronan in the blocking of heparanase-mediated enzymatic and cellular actions. Full article

(This article belongs to the Special Issue Advances in Heparin, Heparan Sulfate and Heparanase)

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11 pages, 1224 KiB

Open AccessArticle

Implications of Heparanase on Heparin Synthesis and Metabolism in Mast Cells

by Marco Maccarana, Juan Jia, Honglian Li, Xiao Zhang, Israel Vlodavsky and Jin-Ping Li

Int. J. Mol. Sci. 2022, 23(9), 4821; https://doi.org/10.3390/ijms23094821 - 27 Apr 2022

Cited by 4 | Viewed by 1992

Abstract

Heparin is a polysaccharide expressed in animal connective tissue-type mast cells. Owing to the special pentasaccharide sequence, heparin specifically binds to antithrombin (AT) and increases the inhibitory activity of AT towards coagulation enzymes. Heparin isolated from porcine intestinal mucosa has an average molecular weight of 15 kDa, while heparins recovered from rat skin and the peritoneal cavity were 60–100 kDa and can be fragmented by the endo-glucuronidase heparanase in vitro. In this study, we have examined heparin isolated from in vitro matured fetal skin mast cells (FSMC) and peritoneal cavity mast cells (PCMC) collected from wildtype (WT), heparanase knockout (Hpa-KO), and heparanase overexpressing (Hpa-tg) mice. The metabolically ³⁵S-labeled heparin products from the mast cells of WT, Hpa-KO, and Hpa-tg mice were compared and analyzed for molecular size and AT-binding activity. The results show that PCMC produced heparins with a size similar to heparin from porcine intestinal mast cells, whilst FSMC produced much longer chains. As expected, heparanase overexpression resulted in the generation of smaller fragments in both cell types, while heparins recovered from heparanase knockout cells were slightly longer than heparin from WT cells. Unexpectedly, we found that heparanase expression affected the production of total glycosaminoglycans (GAGs) and the proportion between heparin and other GAGs but essentially had no effect on heparin catabolism. Full article

(This article belongs to the Special Issue Advances in Heparin, Heparan Sulfate and Heparanase)

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14 pages, 2200 KiB

Open AccessArticle

Acute T-Cell-Driven Inflammation Requires the Endoglycosidase Heparanase-1 from Multiple Cell Types

by Zuopeng Wu, Rebecca A. Sweet, Gerard F. Hoyne, Charmaine J. Simeonovic and Christopher R. Parish

Int. J. Mol. Sci. 2022, 23(9), 4625; https://doi.org/10.3390/ijms23094625 - 21 Apr 2022

Cited by 1 | Viewed by 1836

Abstract

It has been accepted for decades that T lymphocytes and metastasising tumour cells traverse basement membranes (BM) by deploying a battery of degradative enzymes, particularly proteases. However, since many redundant proteases can solubilise BM it has been difficult to prove that proteases aid cell migration, particularly in vivo. Recent studies also suggest that other mechanisms allow BM passage of cells. To resolve this issue we exploited heparanase-1 (HPSE-1), the only endoglycosidase in mammals that digests heparan sulfate (HS), a major constituent of BM. Initially we examined the effect of HPSE-1 deficiency on a well-characterised adoptive transfer model of T-cell-mediated inflammation. We found that total elimination of HPSE-1 from this system resulted in a drastic reduction in tissue injury and loss of target HS. Subsequent studies showed that the source of HPSE-1 in the transferred T cells was predominantly activated CD4⁺ T cells. Based on bone marrow chimeras, two cellular sources of HPSE-1 were identified in T cell recipients, one being haematopoiesis dependent and the other radiation resistant. Collectively our findings unequivocally demonstrate that an acute T-cell-initiated inflammatory response is HPSE-1 dependent and is reliant on HPSE-1 from at least three different cell types. Full article

(This article belongs to the Special Issue Advances in Heparin, Heparan Sulfate and Heparanase)

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18 pages, 6234 KiB

Open AccessArticle

Structure Elucidation of Fucan Sulfate from Sea Cucumber Holothuria fuscopunctata through a Bottom-Up Strategy and the Antioxidant Activity Analysis

by Li Gao, Chen Xu, Xuelin Tao, Zhichuang Zuo, Zimo Ning, Linghui Wang, Na Gao and Jinhua Zhao

Int. J. Mol. Sci. 2022, 23(9), 4488; https://doi.org/10.3390/ijms23094488 - 19 Apr 2022

Cited by 12 | Viewed by 2156

Abstract

Fucan sulfate I (FSI) from the sea cucumber Holothuria fuscopunctata was purified and its structure was clarified based on a bottom-up strategy. The unambiguous structures of a series of oligosaccharides including disaccharides, trisaccharides, and tetrasaccharides, which were released from mild acid hydrolysis of FSI, were identified by one-dimensional (1D)/two-dimensional (2D) nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. All the glycosidic bonds in these oligosaccharides were presented as α1,3 linkages confirmed by correlated signals from their ¹H-¹H ROESY and ¹H-¹³C HMBC spectra. The structural sequence of these oligosaccharides formed by Fuc_2S4S, Fuc_2S, and non-sulfated ones (Fuc_0S), along with the general structural information of FSI, indicated that the structure of FSI could be elucidated as: [-L-Fuc_2S4S-α1,3-L-Fuc_(2S)-α1,3-L-Fuc_2S-α1,3-L-Fuc_0S-α1,3-1-]_n. Moreover, the L-Fuc_0S-α1,3-L-Fuc_2S4S linkage in FSI was susceptible to be cleaved by mild acid hydrolysis. The antioxidant activity assays in vitro showed that FSI and the depolymerized product (dFSI′) had potent activities for superoxide radical scavenging activity with IC₅₀ of 65.71 and 83.72 μg/mL, respectively, while there was no scavenging effect on DPPH, hydroxyl and ABTS radicals. Full article

(This article belongs to the Special Issue Advances in Heparin, Heparan Sulfate and Heparanase)

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15 pages, 44254 KiB

Open AccessArticle

Reversal Activity and Toxicity of Heparin-Binding Copolymer after Subcutaneous Administration of Enoxaparin in Mice

by Justyna Swieton, Joanna Miklosz, Shin-Ichi Yusa, Krzysztof Szczubialka, Dariusz Pawlak, Andrzej Mogielnicki and Bartlomiej Kalaska

Int. J. Mol. Sci. 2021, 22(20), 11149; https://doi.org/10.3390/ijms222011149 - 15 Oct 2021

Cited by 1 | Viewed by 2686

Abstract

Uncontrolled bleeding after enoxaparin (ENX) is rare but may be life-threatening. The only registered antidote for ENX, protamine sulfate (PS), has 60% efficacy and can cause severe adverse side effects. We developed a diblock copolymer, heparin-binding copolymer (HBC), that reverses intravenously administered heparins. Here, we focused on the HBC inhibitory activity against subcutaneously administered ENX in healthy mice. BALB/c mice were subcutaneously injected with ENX at the dose of 5 mg/kg. After 110 min, vehicle, HBC (6.25 and 12.5 mg/kg), or PS (5 and 10 mg/kg) were administered into the tail vein. The blood was collected after 3, 10, 60, 120, 360, and 600 min after vehicle, HBC, or PS administration. The activities of antifactors Xa and IIa and biochemical parameters were measured. The main organs were collected for histological analysis. HBC at the lower dose reversed the effect of ENX on antifactor Xa activity for 10 min after antidote administration, whereas at the higher dose, HBC reversed the effect on antifactor Xa activity throughout the course of the experiment. Both doses of HBC completely reversed the effect of ENX on antifactor IIa activity. PS did not reverse antifactor Xa activity and partially reversed antifactor IIa activity. HBC modulated biochemical parameters. Histopathological analysis showed changes in the liver, lungs, and spleen of mice treated with HBC and in the lungs and heart of mice treated with PS. HBC administered in an appropriate dose might be an efficient substitute for PS to reverse significantly increased anticoagulant activity that may be connected with major bleeding in patients receiving ENX subcutaneously. Full article

(This article belongs to the Special Issue Advances in Heparin, Heparan Sulfate and Heparanase)

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Review

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15 pages, 2355 KiB

Open AccessReview

Importance of Heparan Sulfate Proteoglycans in Pancreatic Islets and β-Cells

by Iwao Takahashi

Int. J. Mol. Sci. 2022, 23(20), 12082; https://doi.org/10.3390/ijms232012082 - 11 Oct 2022

Cited by 2 | Viewed by 2421

Abstract

β-cells in the islets of Langerhans of the pancreas secrete insulin in response to the glucose concentration in the blood. When these pancreatic β-cells are damaged, diabetes develops through glucose intolerance caused by insufficient insulin secretion. High molecular weight polysaccharides, such as heparin and heparan sulfate (HS) proteoglycans, and HS-degrading enzymes, such as heparinase, participate in the protection, maintenance, and enhancement of the functions of pancreatic islets and β-cells, and the demand for studies on glycobiology within the field of diabetes research has increased. This review introduces the roles of complex glycoconjugates containing high molecular weight polysaccharides and their degrading enzymes in pancreatic islets and β-cells, including those obtained in studies conducted by us earlier. In addition, from the perspective of glycobiology, this study proposes the possibility of application to diabetes medicine. Full article

(This article belongs to the Special Issue Advances in Heparin, Heparan Sulfate and Heparanase)

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20 pages, 3058 KiB

Open AccessReview

Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses

by Kohtaro Minami, Hideto Morimoto, Hiroki Morioka, Atsushi Imakiire, Masafumi Kinoshita, Ryuji Yamamoto, Tohru Hirato and Hiroyuki Sonoda

Int. J. Mol. Sci. 2022, 23(19), 11724; https://doi.org/10.3390/ijms231911724 - 3 Oct 2022

Cited by 8 | Viewed by 3216

Abstract

Heparan sulfate (HS) is an essential glycosaminoglycan (GAG) as a component of proteoglycans, which are present on the cell surface and in the extracellular matrix. HS-containing proteoglycans not only function as structural constituents of the basal lamina but also play versatile roles in various physiological processes, including cell signaling and organ development. Thus, inherited mutations of genes associated with the biosynthesis or degradation of HS can cause various diseases, particularly those involving the bones and central nervous system (CNS). Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders involving GAG accumulation throughout the body caused by a deficiency of GAG-degrading enzymes. GAGs are stored differently in different types of MPSs. Particularly, HS deposition is observed in patients with MPS types I, II, III, and VII, all which involve progressive neuropathy with multiple CNS system symptoms. While therapies are available for certain symptoms in some types of MPSs, significant unmet medical needs remain, such as neurocognitive impairment. This review presents recent knowledge on the pathophysiological roles of HS focusing on the pathogenesis of MPSs. We also discuss the possible use and significance of HS as a biomarker for disease severity and therapeutic response in MPSs. Full article

(This article belongs to the Special Issue Advances in Heparin, Heparan Sulfate and Heparanase)

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18 pages, 1402 KiB

Open AccessReview

Heparin and Derivatives for Advanced Cell Therapies

by Sandra Laner-Plamberger, Michaela Oeller, Eva Rohde, Katharina Schallmoser and Dirk Strunk

Int. J. Mol. Sci. 2021, 22(21), 12041; https://doi.org/10.3390/ijms222112041 - 7 Nov 2021

Cited by 9 | Viewed by 4189

Abstract

Heparin and its derivatives are saving thousands of human lives annually, by successfully preventing and treating thromboembolic events. Although the mode of action during anticoagulation is well studied, their influence on cell behavior is not fully understood as is the risk of bleeding and other side effects. New applications in regenerative medicine have evolved supporting production of cell-based therapeutics or as a substrate for creating functionalized matrices in biotechnology. The currently resurgent interest in heparins is related to the expected combined anti-inflammatory, anti-thrombotic and anti-viral action against COVID-19. Based on a concise summary of key biochemical and clinical data, this review summarizes the impact for manufacturing and application of cell therapeutics and highlights the need for discriminating the different heparins. Full article

(This article belongs to the Special Issue Advances in Heparin, Heparan Sulfate and Heparanase)

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15 pages, 1837 KiB

Open AccessReview

Heparin and Its Derivatives: Challenges and Advances in Therapeutic Biomolecules

by Nipa Banik, Seong-Bin Yang, Tae-Bong Kang, Ji-Hong Lim and Jooho Park

Int. J. Mol. Sci. 2021, 22(19), 10524; https://doi.org/10.3390/ijms221910524 - 29 Sep 2021

Cited by 21 | Viewed by 7559

Abstract

Heparin has been extensively studied as a safe medicine and biomolecule over the past few decades. Heparin derivatives, including low-molecular-weight heparins (LMWH) and heparin pentasaccharide, are effective anticoagulants currently used in clinical settings. They have also been studied as functional biomolecules or biomaterials for various therapeutic uses to treat diseases. Heparin, which has a similar molecular structure to heparan sulfate, can be used as a remarkable biomedicine due to its uniquely high safety and biocompatibility. In particular, it has recently drawn attention for use in drug-delivery systems, biomaterial-based tissue engineering, nanoformulations, and new drug-development systems through molecular formulas. A variety of new heparin-based biomolecules and conjugates have been developed in recent years and are currently being evaluated for use in clinical applications. This article reviews heparin derivatives recently studied in the field of drug development for the treatment of various diseases. Full article

(This article belongs to the Special Issue Advances in Heparin, Heparan Sulfate and Heparanase)

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