Heparin oligosaccharide sequence and size essential for inhibition of pulmonary artery smooth muscle cell proliferation

Garg, Hari G.; Cindhuchao, Naiyaratana; Quinn, Deborah A.; Hales, Charles A.; Thanawiroon, Charuwan; Capila, Ishan; Linhardt, Robert J.

doi:10.1016/s0008-6215(02)00190-8

Cited by 13 publications

(12 citation statements)

References 27 publications

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“…The sulfate groups in heparin participate in the molecular conformation and influence the binding with calcium cations (Chevalier et al, 2004 ). They also have a great effect on the anticoagulant activity (Franz and Alban, 1995 ; Garg et al, 2002 ; Huang et al, 2003 ; Liu and Pedersen, 2007 ). The antiproliferative activity of the heparin molecule depends on the molecular size but not on 3- O -sulfo group (Garg et al, 2002 ) and requires both N -acetylation and N -sulfation (Longas et al, 2003 ).…”

Section: Marine Exopolysaccharidesmentioning

confidence: 99%

Exopolysaccharides produced by marine bacteria and their applications as glycosaminoglycan-like molecules

et al. 2014

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Although polysaccharides are ubiquitous and the most abundant renewable bio-components, their studies, covered by the glycochemistry and glycobiology fields, remain a challenge due to their high molecular diversity and complexity. Polysaccharides are industrially used in food products; human therapeutics fall into a more recent research field and pharmaceutical industry is looking for more and more molecules with enhanced activities. Glycosaminoglycans (GAGs) found in animal tissues play a critical role in cellular physiological and pathological processes as they bind many cellular components. Therefore, they present a great potential for the design and preparation of therapeutic drugs. On the other hand, microorganisms producing exopolysaccharides (EPS) are renewable resources meeting well the actual industrial demand. In particular, the diversity of marine microorganisms is still largely unexplored offering great opportunities to discover high value products such as new molecules and biocatalysts. EPS-producing bacteria from the marine environment will be reviewed with a focus on marine-derived EPS from bacteria isolated from deep-sea hydrothermal vents. Information on chemical and structural features, putative pathways of biosynthesis, novel strategies for chemical and enzymatic modifications and potentialities in the biomedical field will be provided. An integrated approach should be used to increase the basic knowledge on these compounds and their applications; new clean environmentally friendly processes for the production of carbohydrate bioactive compounds should also be proposed for a sustainable industry.

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Section: Marine Exopolysaccharidesmentioning

confidence: 99%

Exopolysaccharides produced by marine bacteria and their applications as glycosaminoglycan-like molecules

et al. 2014

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“…In support of this possibility, heparin has anti‐inflammatory and antimetastatic activities ( Seeds et al ., 1995 ; Fryer et al ., 1997 ; Lever & Page, 2002 ), which are distinct from its anticoagulant property that resides within a defined pentasaccharide sequence ( Tyrrell et al ., 1999 ). Furthermore, sulphation, polymer size and anionic charge are reported to be important determinants of the antiproliferative activity of heparin in vascular smooth muscle (VSM) cultured from systemic or pulmonary vascular tissue ( Karnovsky & Edelman, 1994 ; Joseph et al ., 1997 ; Garg et al ., 2000 ; 2002 ). However, the properties responsible for heparin's antiproliferative activity in ASM have been only partially characterised in bovine ASM ( Kilfeather et al ., 1995 ) and have not been examined at all in human ASM.…”

Section: Introductionmentioning

confidence: 99%

Some structural determinants of the antiproliferative effect of heparin‐like molecules on human airway smooth muscle

Kanabar

Hirst

O’Connor

et al. 2005

British J Pharmacology

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1 Accumulation of airway smooth muscle (ASM) and its infiltration by mast cells are key pathological features of airway remodelling in asthma. Heparin, a major component of mast cell granules, inhibits ASM proliferation by an unknown mechanism. Here, unfractionated heparins and related glycosaminoglycans having structurally heterogeneous polysaccharide side chains that varied in molecular weight, sulphation and anionic charge were used to identify features of the heparin molecule that were required for its antiproliferative activity in cultured human ASM cells. 2 Proliferation induced by 10% fetal bovine serum (FBS) was abrogated by two unfractionated commercial heparin preparations (Sigma and Multiparin) and this effect was reproduced with each of three low-molecular weight heparin preparations (3, 5 and 6 kDa, respectively), demonstrating that antiproliferative activity resided in at least a 3 kDa heparin fraction. 3 N-desulphated 20% re-acetylated (N-de) heparin (anticoagulant) and O-desulphated heparin (Ode) (non-anticoagulant) fractions also inhibited FBS-dependent proliferation (rank potency: Sigma heparin4O-de4N-de) suggesting that the antiproliferative action of heparin involved N-sulphation but was independent of its anticoagulant activity. 4 Other sulphated molecules with variable anionic charge (dextran sulphate, fucoidan, chondroitin sulphates A or B, heparan sulphate) inhibited proliferation to varying degrees, as did the nonsulphated molecules hyaluronic acid and poly-L-glutamic acid. However, nonsulphated dextran had no effect. 5 In summary, attenuation of FBS-dependent proliferation of human ASM by heparin involves but does not depend upon sulphation, although loss of N-sulphation reduces antiproliferative activity. This antiproliferative effect is independent of anionic charge and the anticoagulant actions of heparin.

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“…Although a few function-specific heparin/HS motifs have been elucidated, such as the heparin pentasaccharide for binding to antithrombin III and inhibiting coagulation, 13,14 there are numerous other heparin/HS sequences responsible for certain cellular functions that are still unknown. 15,16 The need to better understand the structure/function relationships of HS has driven the development of advanced analytical methods for detailed structural characterization of these biomolecules. 16–18 However, the heterogeneous nature of HS, caused by the postpolymerization modifications during biosynthesis, has made their structure determination a highly challenging task.…”

mentioning

confidence: 99%

“…15,16 The need to better understand the structure/function relationships of HS has driven the development of advanced analytical methods for detailed structural characterization of these biomolecules. 16–18 However, the heterogeneous nature of HS, caused by the postpolymerization modifications during biosynthesis, has made their structure determination a highly challenging task.…”

mentioning

confidence: 99%

De Novo Sequencing of Complex Mixtures of Heparan Sulfate Oligosaccharides

et al. 2016

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Here, we describe the first sequencing method of a complex mixture of heparan sulfate tetrasaccharides by LC-MS/MS. Heparin and heparan sulfate (HS) are linear polysaccharides that are modified in a complex manner by N- and O-sulfation, N-acetylation, and epimerization of the uronic acid. Heparin and HS are involved in various essential cellular communication processes. The structural analysis of these glycosaminoglycans is challenging due to the lability of their sulfate groups, the high heterogeneity of modifications, and the epimerization of the uronic acids. While advances in liquid chromatography (LC) and mass spectrometry (MS) have enabled compositional profiling of HS oligosaccharide mixtures, online separation and detailed structural analysis of isomeric and epimeric HS mixtures has not been achieved. Here, we report the development and evaluation of a chemical derivatization and tandem mass spectrometry method that can separate and identify isomeric and epimeric structures from complex mixtures. A series of well-defined synthetic HS tetrasaccharides varying in sulfation patterns and uronic acid epimerization were analyzed by chemical derivatization and LC-MS/MS. These synthetic compounds made it possible to establish relationships between HS structure, chromatographic behavior and MS/MS fragmentation characteristics. Using the analytical characteristics determined through the analysis of the synthetic HS tetrasaccharide standards, an HS tetrasacharide mixture derived from natural sources was successfully sequenced. This method represents the first sequencing of complex mixtures of HS oligosaccharides, an essential milestone in the analysis of structure-function relationships of these carbohydrates.

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Heparin oligosaccharide sequence and size essential for inhibition of pulmonary artery smooth muscle cell proliferation

Cited by 13 publications

References 27 publications

Exopolysaccharides produced by marine bacteria and their applications as glycosaminoglycan-like molecules

Exopolysaccharides produced by marine bacteria and their applications as glycosaminoglycan-like molecules

Some structural determinants of the antiproliferative effect of heparin‐like molecules on human airway smooth muscle

De Novo Sequencing of Complex Mixtures of Heparan Sulfate Oligosaccharides

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