Some structural determinants of the antiproliferative effect of heparin‐like molecules on human airway smooth muscle
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 glycosaminoglyc...
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| description | 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.
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.
N‐desulphated 20% re‐acetylated (N‐de) heparin (anticoagulant) and O‐desulphated heparin (O‐de) (non‐anticoagulant) fractions also inhibited FBS‐dependent proliferation (rank potency: Sigma heparin>O‐de>N‐de) suggesting that the antiproliferative action of heparin involved N‐sulphation but was independent of its anticoagulant activity.
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 non‐sulphated molecules hyaluronic acid and poly‐L‐glutamic acid. However, nonsulphated dextran had no effect.
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.
British Journal of Pharmacology (2005) 146, 370–377. doi:10.1038/sj.bjp.0706333 |
| doi_str_mv | 10.1038/sj.bjp.0706333 |
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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.
N‐desulphated 20% re‐acetylated (N‐de) heparin (anticoagulant) and O‐desulphated heparin (O‐de) (non‐anticoagulant) fractions also inhibited FBS‐dependent proliferation (rank potency: Sigma heparin>O‐de>N‐de) suggesting that the antiproliferative action of heparin involved N‐sulphation but was independent of its anticoagulant activity.
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 non‐sulphated molecules hyaluronic acid and poly‐L‐glutamic acid. However, nonsulphated dextran had no effect.
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.
British Journal of Pharmacology (2005) 146, 370–377. doi:10.1038/sj.bjp.0706333</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1038/sj.bjp.0706333</identifier><identifier>PMID: 16025136</identifier><identifier>CODEN: BJPCBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Adult ; Aged ; airway ; Biological and medical sciences ; Bronchi ; Cell Proliferation - drug effects ; Cells, Cultured ; Female ; glycosaminoglycan ; Heparin ; Heparin - chemistry ; Heparin - pharmacology ; Heparin, Low-Molecular-Weight ; Heparitin Sulfate - pharmacology ; Humans ; Male ; Medical sciences ; Middle Aged ; Myocytes, Smooth Muscle - cytology ; Myocytes, Smooth Muscle - drug effects ; Pharmacology. Drug treatments ; proliferation ; remodelling ; Sulfates - analysis</subject><ispartof>British journal of pharmacology, 2005-10, Vol.146 (3), p.370-377</ispartof><rights>2005 British Pharmacological Society</rights><rights>2005 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Oct 2005</rights><rights>Copyright 2005, Nature Publishing Group 2005 Nature Publishing Group</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5553-ce4903574ece21650a2cd8f968eccb9bccbc73b4cf1b3a289c41b21130fa66003</citedby><cites>FETCH-LOGICAL-c5553-ce4903574ece21650a2cd8f968eccb9bccbc73b4cf1b3a289c41b21130fa66003</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1576283/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1576283/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,1418,1434,27929,27930,45579,45580,46414,46838,53796,53798</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17150557$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16025136$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kanabar, Varsha</creatorcontrib><creatorcontrib>Hirst, Stuart J</creatorcontrib><creatorcontrib>O'Connor, Brian J</creatorcontrib><creatorcontrib>Page, Clive P</creatorcontrib><title>Some structural determinants of the antiproliferative effect of heparin‐like molecules on human airway smooth muscle</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>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.
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.
N‐desulphated 20% re‐acetylated (N‐de) heparin (anticoagulant) and O‐desulphated heparin (O‐de) (non‐anticoagulant) fractions also inhibited FBS‐dependent proliferation (rank potency: Sigma heparin>O‐de>N‐de) suggesting that the antiproliferative action of heparin involved N‐sulphation but was independent of its anticoagulant activity.
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 non‐sulphated molecules hyaluronic acid and poly‐L‐glutamic acid. However, nonsulphated dextran had no effect.
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.
British Journal of Pharmacology (2005) 146, 370–377. doi:10.1038/sj.bjp.0706333</description><subject>Adult</subject><subject>Aged</subject><subject>airway</subject><subject>Biological and medical sciences</subject><subject>Bronchi</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>Female</subject><subject>glycosaminoglycan</subject><subject>Heparin</subject><subject>Heparin - chemistry</subject><subject>Heparin - pharmacology</subject><subject>Heparin, Low-Molecular-Weight</subject><subject>Heparitin Sulfate - pharmacology</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Myocytes, Smooth Muscle - cytology</subject><subject>Myocytes, Smooth Muscle - drug effects</subject><subject>Pharmacology. 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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.
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.
N‐desulphated 20% re‐acetylated (N‐de) heparin (anticoagulant) and O‐desulphated heparin (O‐de) (non‐anticoagulant) fractions also inhibited FBS‐dependent proliferation (rank potency: Sigma heparin>O‐de>N‐de) suggesting that the antiproliferative action of heparin involved N‐sulphation but was independent of its anticoagulant activity.
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 non‐sulphated molecules hyaluronic acid and poly‐L‐glutamic acid. However, nonsulphated dextran had no effect.
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.
British Journal of Pharmacology (2005) 146, 370–377. doi:10.1038/sj.bjp.0706333</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>16025136</pmid><doi>10.1038/sj.bjp.0706333</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Aged airway Biological and medical sciences Bronchi Cell Proliferation - drug effects Cells, Cultured Female glycosaminoglycan Heparin Heparin - chemistry Heparin - pharmacology Heparin, Low-Molecular-Weight Heparitin Sulfate - pharmacology Humans Male Medical sciences Middle Aged Myocytes, Smooth Muscle - cytology Myocytes, Smooth Muscle - drug effects Pharmacology. Drug treatments proliferation remodelling Sulfates - analysis |
| title | Some structural determinants of the antiproliferative effect of heparin‐like molecules on human airway smooth muscle |
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