Low-sulphated oligosaccharides derived from heparan sulphate inhibit normal angiogenesis

Hahnenberger, Rudolph; Jakobson, Åke; Ansari, Akbar Ali; Wehler, Thomas; Svahn, Carl Magnus; Lindahl, Ulf

doi:10.1093/glycob/3.6.567

Cited by 36 publications

(20 citation statements)

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“…Functionally, this might indicate that vascular basement membranes are capable of binding leukocytes, which constitutively express L-selectin on their cell surface. Other potential important biological activities of vascular HS, to be considered in this context, include anti-proliferative effect on arterial smooth muscle cells (16), inhibition of mesangial cell growth (55), and inhibition of angiogenesis (56).…”

Section: Discussionmentioning

confidence: 99%

Presence of N-Unsubstituted Glucosamine Units in Native Heparan Sulfate Revealed by a Monoclonal Antibody

Born

Gunnarsson

Bakker

et al. 1995

Journal of Biological Chemistry

139

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Proteoglycans consist of one or more glycosaminoglycan side chains covalently bound to a core protein (1, 2). The heparan sulfate proteoglycans (HSPGs) 1 constitute a major class of proteoglycans that are found in the extracellular matrix, especially in basement membranes, and at the cell surface, associated with the cell membrane (3-5). Many biological activities of HSPGs are due to interactions between the heparan sulfate (HS) polysaccharide side chains and a variety of proteins, which include extracellular matrix molecules, enzymes, enzyme inhibitors, growth factors and other cytokines (2, 5-7). These interactions can be specific, dependent on defined sulfation patterns within given sequences of sugar residues, as described for antithrombin (8), basic fibroblast growth factor (9, 10), and hepatocyte growth factor (11); others appear to be mainly based on relatively nonspecific electrostatic interactions, and involve proteins such as lipoprotein lipase (12), platelet factor 4 (13) and mast cell protease I (14) (for a general discussion, see Ref. 15).The biosynthesis of HS involves the formation of a nonsulfated (GlcA␤1,4-GlcNAc␣1,4) n precursor polysaccharide, which subsequently undergoes a series of polymer-modification reactions. These reactions start with N-deacetylation/N-sulfation of GlcNAc residues, which is followed by C-5 epimerization of GlcA to iduronic acid (IdoA) units, and finally by O-sulfation at various positions (5). The GlcA C-5 epimerization and O-sulfation reactions occur in the close vicinity of N-sulfate groups, pointing to a key role for the glucosaminyl N-deacetylase/ N-sulfotransferase enzyme in determining the overall extent of modification of the HS chain. Structural analysis of HS preparations have revealed that the modifications tend to colocalize in block sequences, separated by relatively unmodified domains (16 -19). The extent of biosynthetic modification, affecting the number, length, and substitution patterns of the modified domains as well as their position along the HS chain, may differ among cell types (20), alter during proliferation (21), and change as a result of cell transformation (22,23). Structural analysis of HS is complicated by the fact that even highly purified and uniform preparations consist of mixtures of polysaccharide chains that have reached different levels of modification. Monoclonal antibodies (mAbs) that specifically recognize well defined epitopes in HS could be major tools in such analysis. We recently described the production of such an an-

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Section: Discussionmentioning

confidence: 99%

Presence of N-Unsubstituted Glucosamine Units in Native Heparan Sulfate Revealed by a Monoclonal Antibody

Born

Gunnarsson

Bakker

et al. 1995

Journal of Biological Chemistry

139

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“…Heparin binds to different cell types and to various plasma proteins, thereby modulating their activity [1][2][3][4]. One could therefore argue that the inhibitory effects of LMWH described above might be attributed to its binding to these cytokines.…”

Section: Lmwh Inhibits Production But Does Not Bind Tnf-amentioning

confidence: 99%

“…Beyond its well understood anticoagulant activity, heparin is known to bind and modulate the activity of various proteins, including cell growth and angiogenic factors [1,2], complement components [3] and adhesion molecules [4]. Heparin also exerts anti-inflammatory activities through interacting with different cell types and modulating their proinflammatory activities by interfering with various processes such as migration and cytokine production [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell-dependent cutaneous inflammation

Baram

Rashkovsky

Hershkoviz

et al. 1997

Clinical and Experimental Immunology

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SUMMARYThere has been substantial evidence that suggests that heparin may modulate various aspects of immune function and inflammation in addition to its well known anticoagulant activity. In this regard heparin was found to suppress cell-mediated immune responses or asthmatic reactions to allergen challenge. In the present study we analyse the effects of low molecular weight heparin (LMWH) on mast cell degranulation and cytokine production in vitro and on the elicitation of IgE-mediated mast celldependent late cutaneous allergic inflammation in vivo. We have established that LMWH preferentially inhibited tumour necrosis factor-alpha (TNF-a) and IL-4 production without having any significant effect on mast cell degranulation. These effects have been observed in mast cells derived from three different origins that were activated by either immunological or non-immunological stimuli. We have shown that there is inhibition of TNF-a production (and not neutralization of activity), as elimination of the drug after a short preincubation and addition of LMWH to rTNF-a had no effect on TNF-a-mediated cytotoxic activity. These results were also confirmed by ELISA. In vivo, s.c. injection of the LMWH inhibited the leucocyte infiltration associated with the late cutaneous response which followed passive cutaneous anaphylaxis (PCA) reaction, without affecting mast cell numbers or degranulation. These data suggest that LMWH may have an inhibitory role in mast cell-mediated allergic inflammation, and thus might be considered as a possible therapeutic modality.

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“…Analogous results were obtained on low-sulphated heparan sulphate derivatives by another research group, Hahnenberger R et Al. 1993 [5]. Interestingly this research group found an higher activity in oligosaccharide containing iduronic acid residues ; this exuronic acid is tipically present in heparin more then in heparan sulfate.…”

Section: Discussionmentioning

confidence: 92%

Adhesion inhibition “in vitro” by heparin derivatives correlates with their activity on angiogenesis in mice

Savu

Silvestro²

2003

J Cellular Molecular Medi

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Many diseases are dominated by an anomalous or excessive angiogenesis. Tumor growth and metastasis formation are also angiogenesis dependent. Control of angiogenesis would be of interest if safe and effective angiogenesis inhibitors would be available.Heparin play an important role in angiogenesis and early data showed very promising antiangiogenic effects especially in combination with steroids; unfortunately further studies did not confirm these good results.Moreover the bleeding risks and the need of parenteral administration, reduced the interest on heparin as angiogenesis modulator.In the last years various derivatives of heparin, with different pharmacokinetic and anticoagulant properties have been produced and some of them seems to have interesting antiangiogenic activities in experimental models [1,2].In order to characterize the action of heparin derivatives in the adhesion processes, our group Abstract Heparin (HEP) play an important role in angiogenesis. Inhibition of matrix degrading enzymes and binding to adhesion molecules are some of the interaction mechanism. The bleeding risk and the need of parenteral administration, restrict the therapeutic use of HEP as angiogenesis modulator; presently derivatives, with different pharmacokinetic and anticoagulant properties, are available. In this study the "in vitro" anti-adhesion activity, tested with PMNs and endothelial cells, was compared with the effect on angiogenesis, evaluated in Matrigel implanted mice. Some HEP derivatives, with low anticoagulant activity, showed a significant angiogenesis inhibition. A positive correlation between adhesion inhibition in vitro and anti-angiogenesis effect in vivo was found suggesting that the interaction with adhesion molecules by HEP derivatives play a relevant role in the angiogenesis control.

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Low-sulphated oligosaccharides derived from heparan sulphate inhibit normal angiogenesis

Cited by 36 publications

References 0 publications

Presence of N-Unsubstituted Glucosamine Units in Native Heparan Sulfate Revealed by a Monoclonal Antibody

Presence of N-Unsubstituted Glucosamine Units in Native Heparan Sulfate Revealed by a Monoclonal Antibody

Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell-dependent cutaneous inflammation

Adhesion inhibition “in vitro” by heparin derivatives correlates with their activity on angiogenesis in mice

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