Glycosaminoglycan backbone is not required for the modulation of hemostasis: Effect of different heparin derivatives and non-glycosaminoglycan analogs

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dc.contributor.authorBoucas, Rodrigo I.
dc.contributor.authorJarrouge-Boucas, Thais R.
dc.contributor.authorLima, Marcelo A.
dc.contributor.authorTrindade, Edvaldo S.
dc.contributor.authorMoraes, Fabio A.
dc.contributor.authorCavalheiro, Renan P.
dc.contributor.authorTersariol, Ivarne L. S.
dc.contributor.authorHoppenstead, Debra
dc.contributor.authorFareed, Jawed
dc.contributor.authorNader, Helena B. [UNIFESP]
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniv Fed Parana
dc.contributor.institutionUniv Mogi das Cruzes
dc.contributor.institutionLoyola Med Sch
dc.date.accessioned2016-01-24T14:27:19Z
dc.date.available2016-01-24T14:27:19Z
dc.date.issued2012-06-01
dc.description.abstractHeparin and its derivatives are known to regulate a variety of pathophysiological events related to vascular biology. in the present manuscript we examine a variety of heparinomimetics biochemically (electrophoretic behavior and enzymatic degradation) and pharmacologically (in vitro anticoagulant activity and in vivo hemorrhagic and antithrombotic tests) as well as their interactions with cells from the vessel wall using a time resolved fluorometric method and confocal microscopy. Data were determined for unfractionated heparin (UFH), enoxaparin, synthetic heparin pentasaccharide. C3 heparin derived oligosaccharides and phosphosulfomannan (PI-88). While being structurally distinct from UFH, all compounds exhibited anticoagulant, antithrombotic and hemorrhagic activities. in addition, besides the pentasaccharide, they all stimulated the synthesis of an antithrombotic heparan sulfate present at the cell surface and secreted by endothelial cells. Also, like UFH, they interacted with both endothelial and smooth muscle cells and dislodged UFH from its binding sites in a dose dependent manner but, with distinct saturable curves showing that the binding of polymeric structures to extracellular matrix (ECM) proteins does not depend on a glycosaminoglycan backbone. the data also suggest a common pathway, which does not depend on the presence of the conventionally accepted antithrombin binding pentasaccharide, for ECM dependent activity of the heparinomimetic stimulated synthesis of antithrombotic heparan sulfate. Notably, although of similar molecular weight as well as polymeric backbone, the synthetic heparin pentasaccharide showed significant hemorrhagic action and negligible antithrombotic activity in a venous thrombosis model, contrasting with C3, that displayed negligible hemorrhagic effect and potent antithrombotic action. These results provide evidence that structurally unrelated polymers can elicit similar hemostatic activities and show that polymeric sequence is not always crucial for certain activities. the results also suggest that non-GAG structures may provide an alternative route for the pharmaceutical control of hemostasis. (C) 2012 Elsevier B.V. All rights reserved.en
dc.description.affiliationUniversidade Federal de São Paulo, Dept Biochem, Div Mol Biol, Disciplina Biol Mol, BR-04044020 São Paulo, Brazil
dc.description.affiliationUniv Fed Parana, Dept Biol Celular, BR-81531990 Curitiba, Parana, Brazil
dc.description.affiliationUniv Mogi das Cruzes, Ctr Interdisciplinar Invest, Mogi das Cruzes, Brazil
dc.description.affiliationLoyola Med Sch, Dept Pathol, Maywood, IL USA
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Biochem, Div Mol Biol, Disciplina Biol Mol, BR-04044020 São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.format.extent308-316
dc.identifierhttp://dx.doi.org/10.1016/j.matbio.2012.03.001
dc.identifier.citationMatrix Biology. Amsterdam: Elsevier B.V., v. 31, n. 5, p. 308-316, 2012.
dc.identifier.doi10.1016/j.matbio.2012.03.001
dc.identifier.issn0945-053X
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/34956
dc.identifier.wosWOS:000305768200005
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofMatrix Biology
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.subjectEndothelial cellsen
dc.subjectSmooth muscle cellsen
dc.subjectExtracellular matrixen
dc.subjectAntithrombotic drugsen
dc.subjectHemorrhagic activityen
dc.titleGlycosaminoglycan backbone is not required for the modulation of hemostasis: Effect of different heparin derivatives and non-glycosaminoglycan analogsen
dc.typeinfo:eu-repo/semantics/article
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