Abstract

Heparin from porcine or bovine tissues is used to treat diseases such as venous thrombosis, pulmonary embolism, and coronary artery thrombosis. The anticoagulant effects of heparin result from binding to antithrombin and heparin cofactor II (HCII), which are thereby activated to inhibit thrombin and other coagulation enzymes. Dermatan sulfate is a related polymer that specifically activates HCII. Dermatan sulfates and heparin isolated from the marine invertebrates Styela plicata and Ascidia nigra differ from mammalian glycosaminoglycans in the degree and position of sulfation. These differences have profound effects on their anticoagulant properties in vitro, including their ability to activate antithrombin and HCII. In the present study, ascidian glycosaminoglycans will be compared with their mammalian counterparts to determine the relative contributions of HCII and antithrombin to the antithrombotic activities of heparin and dermatan sulfate.
The specific aims are as follows: (1) Prepare low molecular weight derivatives of ascidian glycosaminoglycans, characterize their structures by nuclear magnetic resonance spectroscopy, and determine their anticoagulant activities in vitro. (2) Compare the anticoagulant properties of ascidian dermatan sulfate and heparin with their low molecular weight derivatives in vivo. (3) Investigate the antithrombotic activity of the ascidian glycosaminoglycans in experimental venous and arterial thrombosis models in rats and in normal or HCII-deficient mice. (4) Study the effects of the ascidian glycosaminoglycans and their low molecular weight derivatives on platelet function and determine the hemorrhagic effects of these polymers in vivo. These studies will provide insight into the antithrombotic mechanisms of glycosaminoglycans and may lead to development of anticoagulants with fewer side effects, improved pharmacokinetics, or greater potency than standard heparin preparations. This research will be done primarily in Brazil as an extension of NIH grant 5 R0l HL 55520-05.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
5R03TW005775-02
Application #
6622188
Study Section
International and Cooperative Projects 1 Study Section (ICP)
Program Officer
Primack, Aron
Project Start
2002-01-01
Project End
2004-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
2
Fiscal Year
2003
Total Cost
$40,320
Indirect Cost

  Institution

Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Belmiro, C L R; Gonçalves, R G; Kozlowski, E O et al. (2011) Dermatan sulfate reduces monocyte chemoattractant protein 1 and TGF-? production, as well as macrophage recruitment and myofibroblast accumulation in mice with unilateral ureteral obstruction. Braz J Med Biol Res 44:624-33
Catlow, Krista R; Deakin, Jon A; Wei, Zheng et al. (2008) Interactions of hepatocyte growth factor/scatter factor with various glycosaminoglycans reveal an important interplay between the presence of iduronate and sulfate density. J Biol Chem 283:5235-48
Santos, Joana C; Mesquita, Juliana M F; Belmiro, Celso L R et al. (2007) Isolation and characterization of a heparin with low antithrombin activity from the body of Styela plicata (Chordata-Tunicata). Distinct effects on venous and arterial models of thrombosis. Thromb Res 121:213-23
Souza, Aline R C; Kozlowski, Eliene O; Cerqueira, Vinicius R et al. (2007) Chondroitin sulfate and keratan sulfate are the major glycosaminoglycans present in the adult zebrafish Danio rerio (Chordata-Cyprinidae). Glycoconj J 24:521-30
Borsig, Lubor; Wang, Lianchun; Cavalcante, Moises C M et al. (2007) Selectin blocking activity of a fucosylated chondroitin sulfate glycosaminoglycan from sea cucumber. Effect on tumor metastasis and neutrophil recruitment. J Biol Chem 282:14984-91
de Barros, Cintia M; Andrade, Leonardo R; Allodi, Silvana et al. (2007) The Hemolymph of the ascidian Styela plicata (Chordata-Tunicata) contains heparin inside basophil-like cells and a unique sulfated galactoglucan in the plasma. J Biol Chem 282:1615-26
Gandra, Mario; Kozlowski, Eliene O; Andrade, Leonardo R et al. (2006) Collagen colocalizes with a protein containing a decorin-specific peptide in the tissues of the ascidian Styela plicata. Comp Biochem Physiol B Biochem Mol Biol 144:215-22
Cardilo-Reis, L; Cavalcante, M C M; Silveira, C B M et al. (2006) In vivo antithrombotic properties of a heparin from the oocyte test cells of the sea squirt Styela plicata(Chordata-Tunicata). Braz J Med Biol Res 39:1409-15
Pecly, Inah M D; Goncalves, Romulo G; Rangel, Ednei P et al. (2006) Effects of low molecular weight heparin in obstructed kidneys: decrease of collagen, fibronectin and TGF-beta, and increase of chondroitin/dermatan sulfate proteoglycans and macrophage infiltration. Nephrol Dial Transplant 21:1212-22
Bao, Xingfeng; Pavao, Mauro S G; Dos Santos, Joana Cabral et al. (2005) A functional dermatan sulfate epitope containing iduronate(2-O-sulfate)alpha1-3GalNAc(6-O-sulfate) disaccharide in the mouse brain: demonstration using a novel monoclonal antibody raised against dermatan sulfate of ascidian Ascidia nigra. J Biol Chem 280:23184-93

Showing the most recent 10 out of 14 publications