HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

Abstract
Heparin 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.
AuthorsRodrigo I Bouças, Thais R Jarrouge-Bouças, Marcelo A Lima, Edvaldo S Trindade, Fabio A Moraes, Renan P Cavalheiro, Ivarne L S Tersariol, Debra Hoppenstead, Jawed Fareed, Helena B Nader
JournalMatrix biology : journal of the International Society for Matrix Biology (Matrix Biol) Vol. 31 Issue 5 Pg. 308-16 (Jun 2012) ISSN: 1569-1802 [Electronic] Netherlands
PMID22504459 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Anticoagulants
  • Fibrinolytic Agents
  • Oligosaccharides
  • phosphomannopentaose sulfate
  • Heparin
  • Heparin Lyase
Topics
  • Animals
  • Anticoagulants (pharmacology)
  • Binding Sites
  • Dose-Response Relationship, Drug
  • Endothelial Cells (chemistry, drug effects)
  • Extracellular Matrix (chemistry, drug effects)
  • Fibrinolytic Agents (pharmacology)
  • Hemostasis
  • Heparin (analogs & derivatives, pharmacology)
  • Heparin Lyase (chemistry)
  • Molecular Weight
  • Myocytes, Smooth Muscle (chemistry, drug effects)
  • Oligosaccharides (pharmacology)
  • Protein Binding
  • Proteolysis
  • Rabbits
  • Rats
  • Substrate Specificity

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: